Esters of 2-deoxy-monosaccharides with anti proliferative activity

ABSTRACT

Compounds and methods of using the same to inhibit glycolysis and treat cancer and other diseases are disclosed.

This application is a continuation of U.S. patent application Ser. No.14/782,521, filed Feb. 16, 2016, which is a national stage entry under35 U.S.C. § 371 of International Application No. PCT/US2014/032942,filed Apr. 4, 2014, which claims the benefit of priority of U.S.Provisional Application No. 61/809,110, filed Apr. 5, 2013. Thedisclosure of which is incorporated by references as if written hereinin their entireties.

The present disclosure relates to highly potent 2-deoxy-monosacharideesters and compositions, and to methods of treating tumor cell growthand inflammatory and/or proliferative dermatological diseases.

Reliance on glycolysis has been correlated with disease progression incancer, and as well as a consistent and significant increase in activityof hexokinase, phosphofructokinase and pyruvate kinase. Hypoxia is alsoa feature of many solid cancers and has been linked to malignanttransformation, metastasis and treatment resistance. Furthermore,glycolysis in cancer cells can be enhanced by certain oncogenes throughthe increased expression of glucose transporters and glycolytic enzymesfound on tumor cells.

Accordingly, the glycolytic pathway has become a potential target forthe selective inhibition of many tumor cells. The inhibition ofglycolysis would be selective for such tumor cells because normal cellsin aerobic conditions would be able to survive such inhibition bygenerating energy through other pathways (e.g., the Krebs cycle, andoxidative phosphorylation). By contrast, when glycolysis is blocked inglycolytic tumor cells, the tumor cells would die because of aninability to utilize the aforementioned pathways.

However, current glycolytic inhibition approaches for cancer treatmentpresent various challenges. For instance, many such treatments are notspecific for the hypoxic environment of tumor cells. More importantly,current treatments are not selective inhibitors of glycolysis. Rather,such treatments can also target other pathways that are essential fornormal cell function, such as glycosylation, where monosaccharides suchas D-mannose form a part of oligosaccharides linked to proteins to formglycoproteins. Among other functions, glycoproteins are essential formaintaining the structural integrity of cell membranes. Thus,interference with glycosylation can have clinical consequences that mayresult in beneficial effects in the treatment of inflammatory andproliferative dermatological diseases as well.

Additionally, research suggests short-chain fatty acids (SCFA's) haveantiproliferative, apoptotic and differentiating properties as well ascan act as inhibitors of histone deacetylases (HDAC). Various SCFA arelinked to the degree of induced histone hyperacetylation is produced viaanaerobic bacterial fermentation within the colon and is thought to beprotective in regard to colon carcinogenesis. Although butyrate (C4) isconsidered the most potent of the SCFA, a variety of other SCFA alsoexist in the colonic lumen. Butyrate is thought to exert its cellulareffects through the induction of histone hyperacetylation. Propionate(C3) and valerate (C5) caused growth arrest and differentiation in humancolon carcinoma cells. In addition, valproic acid has also beensuggested to induce cell differentiation, growth arrest, and apoptosismediated by its histone deacetylases (HDAC)-inhibiting properties.

Thus, there remains a need for improved methods and compositions fortreating proliferative diseases, including cancer and inflammatorydermatological diseases.

Accordingly, the inventors herein disclose new methods and compositionsfor treating proliferative or inflammatory diseases.

Thus, in various embodiments, the present invention provides a method oftreating a proliferative or inflammatory disease in a patient in needthereof comprising administering a therapeutically effective amount ofone or more compounds of the Formula I:

or a salt, ester or prodrug thereof, wherein each R¹, R², R³ and R⁴ areindependently H, or COR⁵; wherein each R⁵ is independently selected fromthe group C₁-C₁₀ straight- or branched-chain alkyl, C₄-C₁₀alkylcycloalkyl, and C₃-C₁₀ cycloalkyl.

In certain embodiments, R² and R³ are COR⁵. In certain embodiments, R₅is independently selected from the group C₃-C₇ straight- orbranched-chain alkyl, C₄-C₁₀ alkylcycloalkyl, and C₃-C₇ cycloalkyl. Inparticular embodiments, the compounds are selected from thoseillustrated in Table 1.

In various embodiments, the proliferative disease is cancer. In certainembodiments, the cancer is brain, lung, breast, colorectal, prostate,gastric, esophageal, colon, pancreatic, ovarian, and/or hematologiccancer. In particular embodiments, the cancer is glioblastoma,high-grade glioma, and metastatic brain cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in vitro dose-response activity for Compound WP1234 in D54,U87, Panc-1, AsPc-1, Colo357-FG, Colo357-L3.6, H226, H352, H441 celllines, and corresponding IC₅₀ values.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

To facilitate understanding of the invention, a number of terms andabbreviations as used herein are defined below as follows:

When introducing elements of the present invention or the preferredembodiment(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The term “and/or” when used in a list of two or more items, means thatany one of the listed items can be employed by itself or in combinationwith any one or more of the listed items. For example, the expression “Aand/or B” is intended to mean either or both of A and B, i.e. A alone, Balone or A and B in combination. The expression “A, B and/or C” isintended to mean A alone, B alone, C alone, A and B in combination, Aand C in combination, B and C in combination or A, B, and C incombination.

The term “about,” as used herein when referring to a measurable valuesuch as an amount of a compound, dose, time, temperature, and the like,is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1%from the specified amount.

The term “proliferative disorder or disease” refers to unwanted cellproliferation of one or more subset of cells in a multicellular organismresulting in harm (i.e., discomfort or decreased life expectancy) to themulticellular organisms. A proliferative disorder or disease can occurin different types of animals and humans. For example, as used herein,“proliferative disorder or disease” includes neoplastic disorders andother proliferative disorders.

The term “neoplastic disorder or disease” or “cancer” refers to a tumorresulting from abnormal or uncontrolled cellular growth. Examples ofneoplastic disorders include, but are not limited to, hematopoieticdisorders, such as the myeloproliferative disorders, thrombocythemia,essential thrombocytosis (ET), angiogenic myeloid metaplasia,myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronicidiopathic myelofibrosis (IMF), polycythemia vera (PV), the cytopenias,and pre-malignant myelodysplastic syndromes; cancers, such as gliomacancers, lung cancers, breast cancers, colorectal cancers, prostatecancers, gastric cancers, esophageal cancers, colon cancers, pancreaticcancers, ovarian cancers, or hematologic malignancies.

As used herein, the term “inflammatory disease” or “inflammatorydisorder” refers to pathological states resulting in inflammation,typically caused by neutrophil chemotaxis. Examples of such disordersinclude inflammatory skin diseases including psoriasis and atopicdermatitis.

The fatty acids that can be used in accordance with the presentinvention comprise a hydrocarbyl portion and a carboxylic acid portion.As used herein, the term “hydrocarbyl” is understood to include“aliphatic,” “cycloaliphatic,” and “aromatic.” The hydrocarbyl groupsare understood to include alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, and alkaryl groups. Further, “hydrocarbyl” is understood toinclude both non-substituted hydrocarbyl groups, and substitutedhydrocarbyl groups, with the latter referring to the hydrocarbon portionbearing additional substituents, besides carbon and hydrogen.Additionally, while “carboxylic acid” is used to refer to the compounds,salts of such acids, i.e., carboxylates, are also expresslycontemplated. Moreover, carboxylic acids and carboxylates may be usedinterchangeably herein.

In particular, fatty acids include, but are not limited to, those havingchain lengths comparable to an unbranched fatty acid of from about 3carbons to about 14 carbons in length. Thus, the chains can be, forexample, from about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbons inlength. The chains can be up to, for example, about 14, 13, 12, 11, 9,8, 7, 6, 5, or 4 carbons in length. The fatty acids can be straight orbranched and can include single, double, and/or triple bonds.Nonlimiting examples of fatty acids include valproate, butyrate,phenylacetate, and phenylbutyrate.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues that it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—)]. Examples ofsuitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,1,4-butadienyl and the like. Unless otherwise specified, the term“alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C≡C—). Examples of alkynyl radicalsinclude ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl,pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unlessotherwise specified, the term “alkynyl” may include “alkynylene” groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C amido” as used herein, alone or in combination, refers to aC(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N amido” asused herein, alone or in combination, refers to a RC(O)N(R′) group, withR and R′ as defined herein or as defined by the specifically enumerated“R” groups designated. The term “acylamino” as used herein, alone or incombination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, any of which may themselves beoptionally substituted. Additionally, R and R′ may combine to formheterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C6H4=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O carbamyl” as used herein, alone or in combination, refers toa OC(O)NRR′, group with R and R′ as defined herein.

The term “N carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′ group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom the group consisting of O, S, and N. In certain embodiments, saidheteroaryl will comprise from 5 to 7 carbon atoms. The term alsoembraces fused polycyclic groups wherein heterocyclic rings are fusedwith aryl rings, wherein heteroaryl rings are fused with otherheteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomsselected from the group consisting of O, S, and N, or 2) bicyclicheteroaryl, wherein each of the fused rings comprises five or six ringmembers, comprising between them one to four heteroatoms selected fromthe group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomsselected from the group consisting of O, S, and N. Examples of lowerheterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls maybe unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, lower alkyl, and lower heteroalkyl, any of whichmay be optionally substituted. Additionally, the R and R′ of a loweramino group may combine to form a five- or six-memberedheterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO2.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO3H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)2-.

The term “sulfonamido” as used herein refers to a compound groupcomprising a sulfonyl group and an amino group, which may be a terminalsubstituent or appear in the middle of a chain. The term “N sulfonamido”refers to a —N(R)S(O)₂R′ group, and “S sulfonamido” refers to a—S(O)₂NRR′ group, with R and R′ as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X3CS(O)2NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X3CS(O)2-group where X isa halogen.

The term “trihalomethoxy” refers to a X3CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH2CH3),fully substituted (e.g., —CF2CF3), monosubstituted (e.g., —CH2CH2F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH2CF3). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R and R′ groups should be understood to be optionallysubstituted as defined herein. Whether an R group has a numberdesignation or not, every R group, including R, R′ and R_(n) where n=(1,2, 3, . . . n), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g. aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“Glycolysis inhibitor” is used herein to refer to a compound thatexhibits an IC50 with respect to glycolytic activity or anticanceractivity of no more than about 100 μM and more typically not more thanabout 50 μM, as measured in the assay name described generally hereinbelow. “IC50” is that concentration of inhibitor that reduces theactivity of glycolysis to half-maximal level. Certain compoundsdisclosed herein have been discovered to exhibit inhibition againstglycolysis. In certain embodiments, compounds will exhibit an IC50 withrespect to glycolysis of no more than about 10 μM; in furtherembodiments, compounds will exhibit an IC50 with respect to glycolysisof no more than about 5 μM; in yet further embodiments, compounds willexhibit an IC50 with respect to glycolysis of not more than about 1 μM;in yet further embodiments, compounds will exhibit an IC50 with respectto glycolysis of not more than about 200 nM, as measured in theglycolysis assay described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. Treatment may also be preemptive in nature, i.e.,it may include prevention of disease. Prevention of a disease mayinvolve complete protection from disease, for example as in the case ofprevention of infection with a pathogen, or may involve prevention ofdisease progression. For example, prevention of a disease may not meancomplete foreclosure of any effect related to the diseases at any level,but instead may mean prevention of the symptoms of a disease to aclinically significant or detectable level. Prevention of diseases mayalso mean prevention of progression of a disease to a later stage of thedisease.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

The present invention includes compounds listed above in the form ofsalts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

A salt of a compound can be made by reacting the appropriate compound inthe form of the free base with the appropriate acid.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations that can be used orally include tablets,push fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances that increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents that increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation or proliferation such as gels, liniments,lotions, creams, ointments or pastes, and drops suitable foradministration to the eye, ear or nose. The active ingredient fortopical administration may comprise, for example, from 0.001% to 10% w/w(by weight) of the formulation. In certain embodiments, the activeingredient may comprise as much as 10% w/w. In other embodiments, it maycomprise less than 5% w/w. In certain embodiments, the active ingredientmay comprise from 2% w/w to 5% w/w. In other embodiments, it maycomprise from 0.1% to 1% w/w of the formulation.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C1-C6) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients that can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, and cosmeticagents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as steric or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example, a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example, those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. In addition, the route ofadministration may vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Alternatively, by way ofexample only, the therapeutic effectiveness of one of the compoundsdescribed herein may be enhanced by administration of an adjuvant (i.e.,by itself the adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Alternatively, by way of exampleonly, the benefit of experienced by a patient may be increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. By way of example only, in a treatment fordiabetes involving administration of one of the compounds describedherein, increased therapeutic benefit may result by also providing thepatient with another therapeutic agent for diabetes. In any case,regardless of the disease, disorder or condition being treated, theoverall benefit experienced by the patient may simply be additive of thetwo therapeutic agents or the patient may experience a synergisticbenefit.

Specific, non-limiting examples of possible combination therapiesinclude use of certain compounds of the invention with celldifferentiating agents, anti-proliferative agents, mitochondrialinhibitors, topical steroids, immunosuppressive compounds, JAK2inhibitors, JAK3 inhibitors, STAT3 inhibitors, STAT5 inhibitors, HIF-1αinhibitors, parathyroid hormone-related protein (PTHrP) agonists, celladhesion blockers, non-steroidal anti-inflammatory agents, antibacterialagents, alkylating agents, anti-metabolite agents, mitotic inhibitors,tyrosine kinase inhibitors, topoisomerase inhibitors, cancerimmunotherapy monoclonal antibodies, anti-tumor antibiotic agents,anti-cancer agents, autophagy-inducing agents, anti-psoriasis drugs,D-mannose, and combinations thereof.

In certain embodiments, cell differentiating agents include, but are notlimited to retinoic acid, retinol, retinal, isotretinoin alitretinoin,etretinate, acitretin, tazarotene, bexarotene, adapalene, vitamin D,alfacalcidol (1-hydroxycholecalciferol), calcitriol(1,25-dihydroxycholecalciferol), cholecalciferol (vitamin D3),dihydrotachysterol (DHT) and ergocalciferol (vitamin D2), phorbolesters, and 12-O-tetradecanoylphorbol-13-acetate.

In certain embodiments, mitochondrial inhibitors include, but are notlimited to, anthraline, dithranol, chrysarobin, and coal tar.

In certain embodiments, topical steroids include, but are not limitedto, clobetasol propionate, betamethasone, betamethasone dipropionate,halobetasol propionate, fluocinonide, diflorasone diacetate, mometasonefuroate, halcinonide, desoximetasone, fluticasone propionate,flurandrenolide, triamcinolone acetonide, fluocinolone acetonide,hydrocortisone, hydrocortisone valerate, prednicarbate, desonide, andalclometasone dipropionate.

In certain embodiments, immunosuppressive compounds include, but are notlimited to, fingolimod, cyclosporine A, azathioprine, dexamethasone,tacrolimus, sirolimus, pimecrolimus, mycophenolate salts, everolimus,basiliximab, daclizumab, anti-thymocyte globulin, anti-lymphocyteglobulin, CTLA4IgG, D-penicillamine, gold salts, hydroxychloroquine,leflunomide, methotrexate, minocycline, sulfasalazine, cyclophosphamide,etanercept, infliximab, adalimumab, anakinra, rituximab, and abatacept.

In certain embodiments, JAK2 inhibitors include, but are not limited to,INCBI8424.

In certain embodiments, JAK3 inhibitors include, but are not limited to,CP-690,550.

In certain embodiments, STAT3 inhibitors include, but are not limitedto, WP1066, WP1193, WP1130, and WP1220/MOL4239.

In certain embodiments, STAT5 inhibitors include, but are not limitedto, WP1220/MOL4239.

In certain embodiments, parathyroid hormone-related protein (PTHrP)agonists include, but are not limited to, PTH(1-34).

In certain embodiments, cell adhesion blockers include, but are notlimited to, bimosiamose.

In certain embodiments, non-steroidal anti-inflammatory agents include,but are not limited to, aceclofenac, acemetacin, amoxiprin, aspirin,azapropazone, benorilate, bromfenac, carprofen, celecoxib, cholinemagnesium salicylate, diclofenac, diflunisal, etodolac, etoracoxib,faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin,ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meloxicam,meclofenamic acid, mefenamic acid, meloxicam, metamizole, methylsalicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinprazone, suprofen, tenoxicam, tiaprofenicacid, and tolmetin.

In certain embodiments, antibacterial agents include, but are notlimited to, amikacin, amoxicillin, ampicillin, arsphenamine,azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin,cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir,cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin,cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clindamycin, cloxacillin, colistin, dalfopristan,demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin,enafloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimicin,imipenem, isoniazide, kanamicin, levofloxacin, linezolid, lomefloxacin,loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,mezlocillin, minocycline, mupirozin, nafcillin, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin,piperacillin, platensimycin, polymixin B, prontocil, pyrazinamide,quinupristine, rifampin, retapamulin, roxithromycin, spectinomycin,streptomycin, sulfacetamide, sulfamethizole, sulfamethoxazole,teicoplanin, telithromycin, tetracycline, ticarcillin, tobramycin,trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

In certain embodiments, alkylating agents include, but are not limitedto, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan,carmustine, fotemustine, lomustine, streptozocin, carboplatin,cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine,temozolomide, thioTEPA, and uramustine.

In certain embodiments, anti-metabolite agents include, but are notlimited to, aminopterin, methotrexate, pemetrexed, raltitrexed,cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin,tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur,capecitabine and gemcitabine.

In certain embodiments, mitotic inhibitors include, but are not limitedto, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, andvinorelbine.

In certain embodiments, tyrosine kinase inhibitors include, but are notlimited to, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, sorafenib, and sunitinib.

In certain embodiments, topoisomerase inhibitors include, but are notlimited to, etoposide, etoposide phosphate, teniposide, camptothecin,topotecan, and irinotecan.

In certain embodiments, cancer immunotherapy monoclonal antibodiesinclude, but are not limited to, rituximab, alemtuzumab, bevacizumab,cetuximab, gemtuzumab, panitumumab, tositumomab, and trastuzumab.

In certain embodiments, anti-tumor antibiotic agents include, but arenot limited to, anthracycline, mithramycin, fludarabine, gemcetobine,daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone,valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, andhydroxyurea.

In certain embodiments, anti-cancer agents include, but are not limitedto, amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine,pentostatin, miltefosine, masoprocol, estramustine, tretinoin,mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane,pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukindiftitox, bortezomib, celecoxib, and anagrelide.

In certain embodiments, autophagy-inducing agents include, but are notlimited to, rapamycin, concanavalin A, eEF-2 kinase inhibitors, andSAHA.

In certain embodiments, anti-psoriasis drugs include, but are notlimited to, AEB071, AIN457, U0267, BIRT 2584, SRT2104, ILV-095, PH-10,tetrathiomolybdate, ASP015K, VB-201, RWJ-445380, botulinum toxin, CF101,CNTO 1275, CTA018, ILV-094, LY2439821, BT061, AMG 827, PTH (1-34),QRX-101, CNTO 1959, CTLA4Ig, AMG 139, and MK-0873.

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

In various embodiments, the present invention provides a method oftreating a proliferative or inflammatory disease in a patient in needthereof comprising administering a therapeutically effective amount ofone or more compounds of the Formula I:

or a salt, ester or prodrug thereof, wherein each R¹, R², R³ and R⁴ areindependently H, or COR⁵; wherein each R⁵ is independently selected fromthe group C₁-C₁₀ straight- or branched-chain alkyl, C₄-C₁₀alkylcycloalkyl, and C₃-C₁₀ cycloalkyl.

In certain embodiments, R² and R³ are COR⁵. In certain embodiments, R₅is independently selected from the group C₃-C₇ straight- orbranched-chain alkyl, C₄-C₁₀ alkylcycloalkyl, and C₃-C₇ cycloalkyl. Inparticular, embodiments, the compounds are selected from thoseillustrated in Table 1.

In various embodiments, the proliferative disease is cancer. In certainembodiments, the cancer is brain, lung, breast, colorectal, prostate,gastric, esophageal, colon, pancreatic, ovarian, and/or hematologiccancer. In particular embodiments, the cancer is glioblastoma,high-grade glioma, and metastatic brain cancer.

Without being bound by theory, it is envisioned that the compoundspresented herein may exert the effects by eliciting autophagy inaddition to, or in lieu of apoptosis. Autophagy is a regulated processin which portions of the cytoplasm are first sequestered withdouble-membrane vesicles known as autophagosomes. Klionsky, D. J., etal., Autophagy as a Regulated Pathway of Cellular Degradation, Science,2000, 290:1717-1721. These autophagosomes then fuse with lysosomes tobecome autolysosomes or degradative autophagic vacuoles, after which thesequestered contents are degraded by lysosomal hydrolases. Autophagyleads to the extensive degradation of organelles, includingmitochondria, which precedes nuclear destruction.

Autophagy is induced in various cell conditions; for example, it isresponsible for the degradation of normal proteins in response tonutrient deprivation, differentiation, aging, transformation, andcancer. Cuervo, A. M., Autophagy: In Sickness and in Health, Trends CellBiol, 2004, 14: 70-77; Shintani, T., et al., Autophagy in Health andDisease: A Double-Edged Sword, Science, 2004, 306: 990-995. In cancerresearch, autophagy is a novel concept, and its role remains unclear. Ingeneral, cancer cells show less autophagic degradation than normalcells. Bursch, W., et al., Programmed Cell Death (PCD). Apoptosis,Autophagic PCD, or Others? Ann. N.Y. Acad. Sci., 2000, 926: 1-12;Ogier-Denis, E., et al., Autophagy: A Barrier or an Adaptive Response toCancer, Biochim Biophys Acta, 2003, 1603: 113-128; Gozuacik, D., et al.,Autophagy as a Cell Death and Tumor Suppressor Mechanism, Oncogene,2004, 23: 2891-2906. Indeed, Beclin1, a mammalian homologue of yeastautophagy-related gene Atg6, plays a role of a tumor suppressor. Liang,X. H., et al., Induction of Autophagy and Inhibition of Tumorigenesis byBeclin 1, Nature, 1999, 402: 672-676; Qu, X., et al., Promotion ofTumorigenesis by Heterozygous Disruption of the Beclin 1 Autophagy Gene,J Clin Invest, 2003, 112:1809-1820; Yue. Z., et al., Beclin 1, anAutophagy Gene Essential For Early Embryonic Development, Is aHaploinsufficient Tumor Suppressor, Proc Natl Acad Sci USA, 2003, 100:15077-15082.

In contrast, numerous cancer treatments have been shown to induceautophagy in established cancer cell lines. Altan, N., et al., DefectiveAcidification in Human Breast Tumor Cells and Implications forChemotherapy, J Exp Med, 1998, 187: 1583-1598; Paglin, S., et al., ANovel Response of Cancer Cells to Radiation Involves Autophagy andFormation of Acidic Vesicles, Cancer Res, 2001, 61: 439-444; Kanzawa,T., et al., Induction of Autophagic Cell Death in Malignant Glioma Cellsby Arsenic Trioxide, Cancer Res, 2003, 63: 2103-2108; Daido, S., et al.,Inhibition of the DNA-Dependent Protein Kinase Catalytic SubunitRadiosensitizes Malignant Glioma Cells by Inducing Autophagy, CancerRes, 2005, 65:4368-4375; Takeuchi, H., et al., Synergistic Augmentationof Rapamycin-Induced Autophagy in Malignant Glioma Cells byPhosphatidylinositol 3-Kinase/Protein Kinase B Inhibitors, Cancer Res,2005, 65:3336-3346. However, whether autophagy helps kill tumor cells orinstead protects them from the treatments' cell-damaging effect is stilldebated. Ogier-Denis, E., et al., Autophagy: A Barrier or an AdaptiveResponse to Cancer, Biochim Biophys Acta, 2003, 1603: 113-128; Gozuacik,D., et al., Autophagy as a Cell Death and Tumor Suppressor Mechanism,Oncogene, 2004, 23: 2891-2906; Edinger, A. L., et al. DefectiveAutophagy Leads to Cancer, Cancer Cell, 2003, 4:422-424; Kondo, Y., etal., Role of Autophagy in Cancer Development and Response to Therapy,Nat Rev Cancer, 2005, 5:726-734; Hait, W. N., et al., A Matter of Lifeor Death (or Both): Understanding Autophagy in Cancer, Clin Cancer Res.,2006 Apr. 1, 12(7 Pt 1):1961-5.

Currently, methods to detect or quantify autophagy are somewhat limited.Demonstration of autophagic vacuoles on electron microscopy is animportant standard; however, this analysis requires considerable skilland is neither easy nor quick. Other assays such as acridine orange ormonodansyl cadaverine staining are not specific to autophagy. Paglin,S., et al., A Novel Response of Cancer Cells to Radiation InvolvesAutophagy and Formation of Acidic Vesicles, Cancer Res, 2001, 61:439-444; Munafo, D. B., et al., A Novel Assay to Study Autophagy:Regulation of Autophagosome Vacuole Size by Amino Acid Deprivation, JCell Sci, 2001, 114:3619-29. The use of the green-fluorescent protein(GFP)-tagged-rat microtubule-associated protein 1 light chain 3 (LC3)expression vector makes autophagy detection specific and easy, but thisassay requires gene transfection and is not available for xenograftmodels or surgical specimens obtained from cancer patients. Kabeya, Y.,et al., LC3, a Mammalian Homologue of Yeast Apg8p, Is Localized inAutophagosome Membranes After Processing, EMBO J, 2000, 19:5720-5728;Mizushima, N., et al., Dissection of Autophagosome Formation UsingApg5-Deficient Mouse Embryonic Stem Cells, J Cell Biol, 2001,152:657-668.

The compounds presented herein are useful to treat a neurodegenerativedisease, such as Alzheimer's disease, or Parkinson's disease.

Furthermore, the compounds and methods that are described herein can beused to prevent or treat Central Nervous System (“CNS”) diseases andconditions such as CNS inflammatory and conditions, e.g., multiplesclerosis and progressive multifocal leukoencephalopathy.

Moreover, the compounds and methods that are described herein can beused to prevent or treat inflammatory diseases and conditions, such asosteoarthritis, Rheumatoid arthritis, Crohn's disease, ulcerativecolitis, and auto-immune diseases such as lupus and mixed auto-immunedisease.

Diseases and conditions such as telangectasia, venous angiomas,hemangioblastoma, and polycythemia vera may also be advantageouslyprevented or treated with the compounds and methods described herein.

These compounds and methods can affect stem cell survival anddifferentiation by maintaining stem cell sternness, e.g., preventing thedifferentiation of stem cells.

The compounds taught herein may also be used for the augmentation ofimmune response, particularly where the augmentation of the immuneresponse leads to the expression of costimulatory molecules on theperipheral macrophages and tumor-infiltrating microglia. These compoundsare also useful when the immune response leads to proliferation ofeffector T cells and/or up-regulation of several key intracellularsignaling molecules that critically regulate T-cell and monocyteactivation. The compounds are useful when the immune responses leads toup-regulation of several key intracellular signaling molecules thatcritically regulate T-cell and monocyte activation, particularlyphosphorylation of Syk (Tyr(352)) in monocytes and ZAP-70 (Tyr (319)) inT cells.

The compounds presented herein to treat cancer may be administered incombination with one or more compounds and/or other agents including butnot limited to anti-cancer agents, anti-angiogenic agents and/orautophagy inducing agents.

Anti-Cancer Agents

Anti-cancer agents that are suitable for use in the methods describedherein include: antitumor antibiotics (anthracyclines, mitoxantrone,bleomycin, mithramycin); Fludarabine, Gemcitabine, temozolomide(Temodar); cyclophosphamides; fluoropyrimidines (such as capecitabine);fluorouracil (5-FU or Adrucil); nitrosoureas, such as procarbazine(Matulane), lomustine, CCNU (CeeBU),3-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-1-(2-chloroethyl)-1-nitroso-ureacarmustine (ACNU), (BCNU, BiCNU, Gliadel Wafer), and estramustine(Emcyt); nitrogen mustard; melphalan; chlorambucil; busulfan; ifosfamidenitrosoureas; thiotepa; antimitotic agents such as vinca alkaloids(e.g., vincristine) and taxoids (e.g., Taxol (paclitaxel)), Taxotere(docetaxel), epothilone analogs, discodermolide analogs, andeleutherobin analogs (e.g., ifosfamide, melphalan, chlorambucil,thiotepa, cisplatin, and carboplatin).

Temodar and other suitable anti-cancer agents may be administered attherapeutically effective dosages under different schedules, asenvisioned by people of ordinary skill in the art. For instance, theanti-cancer agents can be administered at 100 mg per m² body weight forseven consecutive days on a bi-weekly basis. The anti-cancer agents mayalso be administered at the same dosage for 21 days on and 7 days off.Other therapeutic dosages and administration schedules can also beenvisioned by people of ordinary skill in the art.

Anti-Angiogenic Agents

The anti-angiogenic agents useful in the disclosed methods include VEGFinhibitors (e.g., Avastin), VEGF Trap, Sorafenib, Sutent, linomideinhibitors of integrin-αβ3 function, angiostatin, razoxane, and thelike.

Such anti-angiogenic agents may be small molecules, anti-bodies,aptamers, proteins, polypeptides, and other compounds or compositionsthat reduce or eliminate angiogenic activity. Anti-angiogenic agents maybe administered at a therapeutically effective dose under differentschedules. As an example, Avastin may be administered to a patient at adose of 5, 10 or 15 mg per kg body weight once every two or three weeks.Alternatively, 3-20 mg/kg once every 2-3 weeks is suitable.

Autophagy-Inducing Agents

One or more autophagy-inducing agents may also be used in the methodspresented herein. For instance, Rapamycin is useful as anautophagy-inducing agent. Other autophagy-inducing agents includeconcanavalin A, inhibitors of eEF-2 Kinase Inhibitors and histonedeactylase inhibitors like SAHA.

The basis for adding one or more autophagy inducing agents to thecombination therapies of the present invention is that our resultsindicate that sugar-based inhibitors of glycolysis kill tumor cellsthrough this process. Autophagy is a regulated process in which portionsof the cytoplasm are first sequestered with double-membrane vesiclesknown as autophagosomes. Klionsky, D. J., et al., Autophagy as aRegulated Pathway of Cellular Degradation, Science, 2000, 290:1717-1721.These autophagosomes then fuse with lysosomes to become autolysosomes ordegradative autophagic vacuoles, after which the sequestered contentsare degraded by lysosomal hydrolases. Autophagy leads to the extensivedegradation of organelles, including mitochondria, which precedesnuclear destruction.

Autophagy is induced in various cell conditions; for example, it isresponsible for the degradation of normal proteins in response tonutrient deprivation, differentiation, aging, transformation, andcancer. Cuervo, A. M., Autophagy: In Sickness and in Health, Trends CellBiol, 2004, 14: 70-77; Shintani, T., et al., Autophagy in Health andDisease: A Double-Edged Sword, Science, 2004, 306: 990-995. In cancerresearch, autophagy is a novel concept, and its role remains unclear. Ingeneral, cancer cells show less autophagic degradation than normalcells. Bursch, W., et al., Programmed Cell Death (PCD). Apoptosis,Autophagic PCD, or Others? Ann. N.Y. Acad. Sci., 2000, 926: 1-12;Ogier-Denis, E., et al., Autophagy: A Barrier or an Adaptive Response toCancer, Biochim Biophys Acta, 2003, 1603: 113-128; Gozuacik, D., et al.,Autophagy as a Cell Death and Tumor Suppressor Mechanism, Oncogene,2004, 23: 2891-2906. Indeed, Beclin1, a mammalian homologue of yeastautophagy-related gene Atg6, plays a role of a tumor suppressor. Liang,X. H., et al., Induction of Autophagy and Inhibition of Tumorigenesis byBeclin 1, Nature, 1999, 402: 672-676; Qu, X., et al., Promotion ofTumorigenesis by Heterozygous Disruption of the Beclin 1 Autophagy Gene,J Clin Invest, 2003, 112:1809-1820; Yue. Z., et al., Beclin 1, anAutophagy Gene Essential For Early Embryonic Development, Is aHaploinsufficient Tumor Suppressor, Proc Natl Acad Sci USA, 2003, 100:15077-15082.

The combination therapies of the present invention are particularlysuitable for treating brain tumors including primary tumors such asglioblastoma or high-grade gliomas, and secondary brain tumors such asmetastatic brain tumors. One unique property of the CNS is its strikingpredilection to uptake glucose and its analogs.

Hypoglycemic Agents

It is further envisioned that more optimal results will be obtained withthe combination therapies if the patient is also treated with atherapeutically effective amount of one or more hypoglycemic agentsunder different schedules, preferably before treatment with compoundsdescribed herein. Hypoglycemic agents suitable for the present inventioninclude compounds that reduce blood glucose levels. Non-limitingexamples of such compounds include insulin, alpha-glucosidaseinhibitors, sulfonylureas, meglitinides, D-phenylalanine derivatives,biguanides, thiazolidinediones, GLP-1 analogues, DPP-4 Inhibitors, andthe like.

Thus, in another aspect, certain embodiments provide methods fortreating proliferative or inflammatory disease in a human or animalsubject in need of such treatment comprising administering to saidsubject an amount of a compound disclosed herein effective to reduce orprevent said disease in the subject, in combination with at least oneadditional agent for the treatment of said disease that is known in theart. In a related aspect, certain embodiments provide therapeuticcompositions comprising at least one compound disclosed herein incombination with one or more additional agents for the treatment ofinflammatory proliferative or inflammatory diseases.

Specific diseases to be treated by the compounds, compositions, andmethods disclosed herein include, but are not limited to, proliferativeor inflammatory diseases, psoriasis, plaque psoriasis, psoriasisvulgaris, localized pustular psoriasis, pustule psoriasis, Hallopeaulocalized continuous achrodermatitis, pustular palm psoriasis, pustularsole psoriasis, generalized pustular psoriasis, von Zumbuch generalizedpustular psoriasis, milia psoriasis, Hallopeau generalized continuousdermatitis, herpetiform impetigodermatitis, atopic dermatitis,seborrheic dermatitis, contact dermatitis, numular dermatitis,generalized exfoliative dermatitis, statis dermatitis, perioraldermatitis, acne, rosacea, boils, carbuncles, pemphigus, cellulitis,Grover's disease, hidradenitis suppurativa, lichen planus, chroniclichen simplex, rhinophyma, pseudofolliculitis barbae, inflammatoryreactions, drug eruptions, erythema, erythema multiforme, erythemanodosum, granuloma annulare, eczema, xerosis, terosis, ichthyosis,epidermolytic hyperkeratosis, keratoses, pruritis, cradle cap, scales,fresh stretch marks, dermatoses, burns, skin hypersensitivity reactions(including poison ivy and poison oak), decubitus ulcers, pressureulcers, diabetic ulcers, epidermolysis bullosa, eczematoid dermatitis,pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedema, vasculitides, dermal eosinophilia, vitiligo, alopeciaareata, skin cancers, cutaneous T cell lymphoma, basal cell carcinoma,nodular basal cell carcinoma, cystic basal cell carcinoma, cicatricialbasal cell carcinoma, infiltrative basal cell carcinoma, Micronodularbasal cell carcinoma, superficial basal cell carcinoma, pigmented basalcell carcinoma, Jacobi ulcer, fibroepithelioma of Pinkus, polypoid basalcell carcinoma, pore-like basal cell carcinoma, aberrant basal cellcarcinoma, squamous cell carcinoma, adenoid squamous cell carcinoma,clear cell squamous cell carcinoma, spindle cell squamous cellcarcinoma, signet-ring cell squamous cell carcinoma, basaloid squamouscell carcinoma, verrucous carcinoma, keratoacanthoma, Bowen's disease,Marjolin's ulcer, melanoma, lentigo maligna, lentigo maligna melanoma,superficial spreading melanoma, acral lentiginous melanoma, mucosalmelanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma,amelanotic melanoma, soft-tissue melanoma, dermatofibrosarcomaprotuberans, Merkel cell carcinoma, Kaposi's sarcoma, spindle celltumors, sebaceous carcinomas, microcystic adnexal carcinoma, Pagets'sdisease, atypical fibroxanthoma, leimyosarcoma, angiosarcoma, and Merkelcell carcinoma.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Methods

General Synthetic Methods for Preparing Compounds

The compounds disclosed herein can be synthesized according to theprocedures described in WO 2010005799 (paragraphs [0086]-[0145]); WO2009108926 (paragraphs [0173]-[0185]); WO 2008131024 (paragraphs[0067]-[0072]); US 20100152121 (paragraphs [0067]-[0083]); U.S. Pat. No.7,160,865 (columns 11-13); and U.S. Pat. No. 6,979,675 (columns 28-29),the disclosures of which are hereby incorporated by reference as ifwritten herein in their entireties.

Examples

The invention is further illustrated by the following examples.

Synthesis of 1-O-acyl-2-deoxy-D-glucopyranose

3,4,6-Tri-O-Benzyl-2-Deoxy-D-Glucopyranose

Solution of 2-deoxy-D-glucopyranose (1.46 g, 10 mmol) in DMF (15 mL) wasprepared and cooled down to −10° C. Sodium hydride (60% suspension inmineral oil) (1.99 g, 50 mmol) was added and the mixture was stirred for30 min. Benzyl bromide (6.85 g, 40 mmol) was added, the cooling bath wasremoved and the reaction mixture was stirred at room temperature untilall substrate was converted into product. The mixture was cooled down to0° C., and water (50 ml) was added slowly, followed by DCM (50 mL).Organic layer was separated, washed with water until neutral, then withbrine, and dried over anhydrous sodium sulfate. Drying agent andsolvents were removed and product was purified by low pressure columnchromatography (LPC), using hexanes:ethyl acetate gradient (0 to 20% ofEtOAc) for elution.

Fractions contained product were pooled together, evaporated to drynessand dried under reduced pressure to give 3.03 g of product. Yield 73%,

¹H NMR (CDCl₃, 6), ppm: 7.34-7.24 (m, 15H, H arom.), 6.43 (dd, 1H, J=6.1Hz, J=1.1 Hz, H-1), 4.88 (dd, 1H, J=6.1 Hz, J=2.7 Hz, H-2), 4.84 (d, 1H,J=11.4 Hz, CH₂Ph), 4.67-4.54 (m, 5H, CH₂Ph), 4.22 (m, 1H, H-3), 4.07(ddd, 1H, J=8.2 Hz, J=4.7 Hz, J=3.2 Hz, H-5), 3.87 (dd, 1H, J=6.2 Hz,J=8.6 Hz, H-4), 3.81 (dd, 1H, J=4.9 Hz, J=10.9 Hz, H-6), 3.76 (dd, 1H,J=3.1 Hz, J=10.9 Hz, H-6′).

3,4,6-Tri-O-Benzyl-2-Deoxy-D-Glucopyranose

48% Hydrobromic acid (0.5 mL, 4.5 mmol) was added to a solution of3,4,6-tri-O-benzyl-D-glucal (2.08 g, 5 mmol) in THF (50 mL), andobtained mixture was stirred at room temperature for 20 min., (TLCcontrol). After reaction was completed water (20 mL) followed by sodiumcarbonate (2.25 mmol, 239 mg) were added and the mixture was stirred foradditional 10 min. The reaction mixture was extracted with ethyl acetate(3×30 mL). Combined organic extracts were washed with water untilneutral and dried over sodium sulfate. Drying agent and solvents wereremoved and product was purified by crystallization (ethylacetate/hexanes)Yield 76%, α:β ratio=3:1

¹H NMR (CDCl₃, 6), ppm: 7.38-7.14 (m, 30H, H arom.α, β), 5.40 (m, 1H,H-1α), 4.89 (d, 1H, J=10.9 Hz, CH₂Ph α), 4.88 (d, 1H, J=10.9 Hz, CH₂Phβ), 4.77 (m, 1H, H-1β), 4.70-4.50 (m, 9H, CH₂Ph α, CH₂Ph β), 4.08-4.00(m, 2H, H-3α, H-5α), 3.75-3.60 (m, 5H, H-6α, H-6β, H-6′α, H-6′β), 3.50(m, 3H, H-4α, H-4β, H-5β), 3.26 (d, 1H, J=6.3 Hz, OH β), 2.66 (m, 1H, OHα), 2.37 (ddd, 1H, J=12.5, Hz, J=5.1 Hz, J=2.2 Hz, H-2eβ), 2.29 (dd, 1H,J=12.9 Hz, J=5.0 Hz, H-2eα), 1.69 (dd, 1H, J=J=12.4 Hz, H-2aα), 1.57(ddd, 1H, J=J=12.1 Hz, J=9.7 Hz, H-2aβ).

1-O-Acyl-3,4,6-Tri-O-Benzyl-2-Deoxy-D-Glucopyranose—General Procedure

Solution of 3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranose (4.34 g, 10 mmol)and pyridine (1.62 mL, 20 mmol) in DCM (30 mL) was prepared and cooleddown to 0° C. Acyl chloride (11 mmol) was slowly added and the mixturewas stirred in room temperature overnight. DCM (50 mL), was added andthe reaction mixture was washed with water (2×30 mL), brine (40 mL) thendried over sodium sulfate. Drying agent and solvents were removed andproduct was purified by LPC using hexanes:ethyl acetate gradient (0 to20% of AcOEt) for elution. Fractions contained product were pooledtogether, evaporated to dryness and dried under reduced pressure.Following compounds were prepared according to this procedure:

3,4,6-Tri-O-Benzyl-1-O-Butyryl-2-Deoxy-D-Glucopyranose

Yield 92%, α:β ratio=2:1

¹H NMR (CDCl₃, 6) ppm: 7.38-7.19 (m, 30H, Harom. α,β), 6.31 (m, 1H,H-1α), 5.73 (dd, 1H, J=10.0 Hz, J=2.1 Hz, H-1β), 4.93 (d, 1H, J=10.7 Hz,CH₂Ph), 4.91 (d, 1H, J=10.7 Hz, CH₂Ph), 4.73-4.51 (m, 10H, CH₂Ph a 1),3.97 (ddd, 1H, J=11.5 Hz, J=8.6 Hz, J=5.0 Hz, H-3α), 3.87 (ddd, 1H,J=10.0 Hz, J=3.6 Hz, J=2.2 Hz, H-5α), 3.83-3.63 (m, 7H, H-6α, H-6β,H-6′α, H-6′β, H-4α, H-4β, H-3β), 3.55 (ddd, 1H, J=9.2 Hz, J=3.5 Hz,J=2.3 Hz, H-5β), 2.43-2.27 (m, 6H, H-2eα, H-2eβ, CH₂COα, CH₂COβ), 1.87(ddd, 1H, J=13.6 Hz, J=11.4 Hz, J=3.4, H-2α) 1.80-1.58 (m, 5H, CH₂α,CH₂₄, H-2aβ), 0.98 (t, 3H, J=7.6 Hz, CH₃β), 0.95 (t, 3H, J=7.6 Hz, CH₃).

3,4,6-Tri-O-Benzyl-1-O-(2-Ethyl)Butyryl-2-Deoxy-β-D-Glucopyranose

Yield 79%

¹H NMR (CDCl₃, δ) ppm: 7.38-7.17 (m, 15H, Harom.), 5.74 (dd, 1H, J=10.0Hz, J=2.2 Hz, H-1), 4.91 (d, 1H, J=10.8 Hz, CH₂Ph), 4.72 (d, 1H, J=11.6Hz, CH₂Ph), 4.65-4.51 (m, 4H, CH₂Ph), 3.82-3.70 (m, 3H, H-3, H□6□□H□6□),3.65 (dd, 1H, J=9.6 Hz, J=9.4 Hz, H-4), 3.54 (ddd, 1H, J=9.4 Hz, J=J=2.6Hz, H-5), 2.39 (ddd, 1H, J=12.3 Hz, J=4.8 Hz, J=2.1 Hz, H-2e), 2.34-2.23(m, 1H, CHCO), 1.84-1.45 (m, 5H, H-2a, 2CH₂), 1.00-0.85 (M, 6H, 2CH₃)

3,4,6-Tri-O-Benzyl-1-O-Valproyl-2-Deoxy-β-D-Glucopyranose

Yield 73%

¹H NMR (CDCl₃, δ) ppm: 7.38-7.17 (m, 15H, Harom.), 5.73 (dd, 1H, J=10.0Hz, J=2.1 Hz, H-1), 4.89 (d, 1H, J=10.9 Hz, CH₂Ph), 4.70 (d, 1H, J=11.6Hz, CH₂Ph), 4.65-4.51 (m, 4H, CH₂Ph), 3.79-3.67 (m, 3H, H-3, H□6□□H□6□),3.63 (dd, 1H, J=8.6 Hz, J=9.3 Hz, H-4), 3.51 (ddd, 1H, J=9.3 Hz, J=3.3Hz, J=2.6 Hz, H-5), 2.46-2.30 (m, 2H, H-2e, CHCO), 1.81-1.21 (m, 9H,H-2α, CH₂) 0.90 (t, 3H, J=7.2 Hz, CH₃)

1-O-Acyl-2-Deoxy-D-Glucopyranose—General Procedure

Pd/C Degussa type (10% (50% wet)) (0.4 g) was added to the solution of1-O-acyl-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranose (5 mmol) in ethanol(50 mL). Obtained mixture was hydrogenated at room temperature usingPaar apparatus with hydrogen (45 psi). After reaction was completed (TLCcontrol), catalyst was filtered off and the solvent was evaporated todryness to give a crude product. Product was purified by LPC usingchloroform:methanol gradient (0-10% of MeOH) for elution. Fractionscontained product were pooled together, evaporated to dryness and driedunder reduced pressure.

Following compounds were prepared according to this procedure:

1-O-Butyryl-2-Deoxy-D-Glucopyranose (WP1212)

Yield 82%, α:β ratio=3.4:1, [α]^(D)+74°, (c=1.26, methanol)

¹H NMR (DMSO-d6, δ) ppm: 6.07 (d, 1H, J=2.1 Hz, H-1α), 5.63 (dd, 1H,J=10.1 Hz, J=2.1 Hz, H-1β), 5.00 (d, 1H, J=5.4 Hz, OHα), 4.96 (d, 1H,J=4.9 Hz, OHβ), 4.93 (d, 1H, J=5.1 Hz, OHβ), 4.89 (d, 1H, J=4.9 Hz,OHα), 4.52 (dd, 1H, J=J=6.1 Hz, OHβ), 4.48 (dd, 1H, J=5.6 Hz, J=6.1 Hz,OH), 3.70-3.38 (m, 8H, H-3α, H-3β, H-5α, H-5β, H-6α, H-6β), 3.14 (ddd,1H, J=J=9.2 Hz, J=5.3 Hz, H-4α), 3.03 (ddd, 1H, J=J=9.2 Hz, J=5.0 Hz,H-4β), 2.01 (dd, 2H, J=J=7.5 Hz, CH₂COα, CH₂COP), 2.01 (ddd, 1H, J=12.3Hz, J=5.0 Hz, J=2.1 Hz, H-2eβ), 1.93 (ddd, 1H, J=12.7 Hz, J=5.0 Hz,J=1.4 Hz, H-2eα), 1.63-1.50 (m, 5H, CH₂α, CH₂β, H-2aα), 1.45 (ddd, 1H,J=13.6 Hz, J=J=11.7 Hz, H-2aβ), 1.11 (dd, 1H, J=7.1 Hz, J=4.0 Hz, CH₂β)1.03 (t, 3H, J=7.5 Hz, CH₃α), 1.02 (t, 3H, J=7.5 Hz, CH₃α)

1-O-Valproyl-2-Deoxy-β-D-Glucopyranose (WP1490)

Yield 76%,

¹H NMR (DMSO-d6, δ) ppm: 5.60 (d, 1H, J=9.9 Hz, H-1), 3.63 (d, 1H,J=11.8 Hz, H-6), 3.53-3.42 (m, 2H, H-3, H-6), 3.17-3.12 (m, 1H, H-5),3.02 (dd, 1H, J=9.0 Hz, J=9.2 Hz, H-4), 2.35-2.27 (m, 1H, CHCO), 1.99(ddd, 1H, J=12.0, J=4.6 Hz, J=2.1 Hz, H-2e), 1.57-1.32 (m, 5H, H-2α,2CH₂), 1.28-1.18 (m, 4H, 2CH₂), 0.83 (t, 6H, 2CH₃)

1-O-(2-Ethyl)Butyryl-2-Deoxy-β-D-Glucopyranose (WP1474)

Yield %,

¹H NMR (DMSO-d6+D₂O, δ) ppm: 5.64 (d, 1H, J=9.9 Hz, H-1), 3.64 (d, 1H,J=11.8 Hz, H-6), 3.51-3.39 (m, 2H, H-3, H-6), 3.15 (ddd, 1H, J=9.4 Hz,J=5.3 Hz, J=1.7 Hz, H-5), 3.03 (dd, 1H, J=9.2 Hz, J=8.9 Hz, H-4),2.23-2.15 (m, 1H, CHCO), 2.00 (ddd, 1H, J=12.0, J=4.7 Hz, J=1.7 Hz,H-2e), 1.56-1.44 (m, 5H, H-2α, 2CH₂), 0.84 (t, 3H, J=7.2 Hz, CH₃), 0.83(t, 3H, J=7.4 Hz, CH₃)

Synthesis of 3-O-Valproyl-2-Deoxy-D-Glucopyranose

Synthesis of 4,6-Di-Benzyl-3-O-Valproyl-2-Deoxy-D-Glucopyranose

4,6-di-O-benzyl-2-deoxy-D-glucopyranose (2.0 g, 6.1 mmol) was dissolvedin DCM (20 mL). Pyridine (14 mmol, 1.2 mL) followed by valproyl chloride(9.2 mmol, 1.6 mL) was added and obtained mixture was stirred at roomtemperature. After reaction was completed (TLC control), the mixture wasdiluted with DCM (100 mL) and washed with water (2×40 mL), then withbrine, and dried over anhydrous Na₂SO₄. Drying agent and solvent wereremoved and product was purified by LPC using hexanes:ethyl acetategradient (0-10% of AcOEt) for elution. Fractions contained product werepooled together and evaporated to dryness to give 2.76 g (6.1 mmol,yield 100%) of pure product.

¹H NMR (CDCl₃, 500 MHz, 6) ppm: 7.38-7.22 (m, 10H, Harom.), 6.44 (d, 1H,J=6.0 Hz, H-1), 5.43 (m, 1H, H-3), 4.78 (dd, 1H, J=6.0 Hz, J=2.9 Hz,H-2), 4.74 (d, 1H, J=11.3 Hz, CH₂-Ph), 4.62 (d, 1H, J=11.3 Hz, CH₂Ph),4.61 (d, 1H, J=12.2 Hz, CH₂Ph), 4.56 (d, 1H, J=12.2 Hz, CH₂Ph), 4.11(ddd, 1H, J=8.0 Hz, J=4.6 Hz, J=2.7 Hz, H-5), 3.93 (dd, 1H, J=8.4 Hz,J=8.0 Hz, H-4), 3.82 (dd, 1H, J=10.8 Hz, J=4.6 Hz, H-6), 3.73 (dd, 1H,J=10.8 Hz, J=2.7 Hz, H-6′), 2.35 (h, 1H, J=6.1 Hz, CHCO), 1.65-1.55 (m,2H, CH₂), 1.46-1.36 (m, 2H, CH₂), 1.34-1.24 (m, 4H, CH₂), 0.87 (t, 3H,J=9.0 Hz, CH₃), 0.85 (t, 3H, J=8.3 Hz, CH₃)

Synthesis of 4,6-Di-Benzyl-3-O-Valproyl-2-Deoxy-α-D-Glucopyranose

4,6-Di-benzyl-3-O-valproyl-2-deoxy-D-glucopyranose (2.76 g, 6.1 mmol)was dissolved in THF (30 mL). 48% HBr (water solution) (0.5 mL, 4.5mmol) was added and the reaction mixture was stirred at roomtemperature. After reaction was completed (TLC control), the reactionmixture was diluted with water (15 mL). The mixture was neutralized byaddition of solid Na₂CO₃ (2.25 mmol, 238.5 mg) and water (30 mL). THFwas evaporated and residue was dissolved in ethyl acetate (100 mL).Organic solution was washed with water, then with brine, and dried overanhydrous Na₂SO₄. Drying agent and solvent was removed under reducedpressure and product was purified by LPC using hexanes:ethyl acetategradient (0-20% of AcOEt) for elution. Fractions contained product werepooled together and evaporated to dryness to give 1.8 g (3.8 mmol)(yield 62.8%) of 4,6-di-benzyl-3-O-valproyl-2-deoxy-D-glucopyranose

¹H NMR (CDCl₃, 500 MHz, 6) ppm: 7.38-7.12 (m, 10H, Harom.), 5.39 (bs,1H, H-1), 5.37 (ddd, 1H, J=12.1 Hz, J=9.0 Hz, J=5.0 Hz, H-3), 4.73 (d,1H, J=11.1 Hz, CH₂Ph), 4.61 (d, 1H, J=12.2 Hz, CH₂Ph), 4.51 (d, 1H,J=12.2 Hz, CH₂Ph), 4.49 (d, 1H, J=11.1 Hz, CH₂Ph), 4.10 (ddd, 1H, J=9.8Hz, J=4.2 Hz, J=2.1 Hz, H-5), 3.72 (dd, 1H, J=10.6 Hz, J=4.3 Hz, H-6),3.65 (dd, 1H, J=10.6 Hz, J=2.0 Hz, H-6′), 3.64 (dd, 1H, J=J=9.8 Hz,H-4), 2.74 (bs, 1H, OH), 2.41-2.28 (m, 2H, H-2a, CHCO), 1.71 (ddd, 1H,J=11.0 Hz, J=3.6 Hz, J=2.0 Hz, H-2e), 1.64-1.18 (m, 8H, CH₂), 0.85 (t,3H, J=7.2 Hz, CH₃), 0.82 (t, 3H, J=7.2 Hz, CH₃)

3-O-Valproyl-2-Deoxy-D-Glucopyranose (WP1512)

Pd/C Degussa type (10% (50% wet)) (0.145 g) was added to the solution of4,6-di-O-benzyl-3-O-valproyl-D-glucopyranose (0.6 g) in THF (12 mL).Obtained mixture was hydrogenated at room temperature using Paarapparatus with hydrogen (48 psi). After reaction was completed (TLCcontrol), catalyst was filtered off and the solvent was evaporated todryness. Product was purified by LPC using gradient CHCl₃: MeOH (0 to10% of MeOH) as eluent. Fractions contained product were pooledtogether, evaporated to dryness and dried under reduced pressure, togive pure product.

Yield %, α:β ratio=2:1

¹H NMR (DMSO-d6, δ) ppm: 5.14 (bs, 1H, H-1α), 5.01 (ddd, 1H, J=J=10.5Hz, J=5.0 Hz, H-3α), 4.69 (m, 2H, J=9.3 Hz, H-1β, H-3β), 3.67-3.61 (m,1H, H-5α), 3.60 (d, 1H, J=11.8 Hz, H-6α), 3.55-3.45 (m, 3H, H-6′α, H-6β,H-6′β), 3.28 (dd, 1H, J=9.6 Hz, J=9.5 Hz, H-4α), 3.21 (dd, 1H, J=9.5 Hz,J=9.1 Hz, H-4β), 3.17-3.12 (m, 1H, H-5β), 2.32-2.24 (m, 2H, CHCOα,CHCOβ), 2.00 (dd, 1H, J=11.4 Hz, J=4.4 Hz, H-2eβ), 1.88 (dd, 1H, J=12.4Hz, J=5.0 Hz, H-2eα), 1.52 (m, 18H, H-2aα, H-2α, 4CH₂α, 4CH₂β), 0.82(t□□12H, J=7.2 Hz, 2CH₃α, 2CH₃β)

Synthesis of 3-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose

Synthesis of4-O-Benzyl-3-O-(2-Ethyl)Butyryl-6-O-Tert-Butyldimethylsilyl-2-Deoxy-D-Glucopyranose

3-O-benzyl-6-O-tert-butyldimethylsilyl-2-deoxy-D-glucopyranose (3 mmol)and pyridine (6 mmol) were dissolved in dichloromethane (20 mL). Thereaction mixture was cooled down to 0° C. (2-ethyl)butyryl chloride (4.5mmol) was added. The reaction mixture was stirred at room temperaturefor 1 hr, then it was diluted with DCM (50 mL), washed with water (3×50mL), and dried over anhydrous sodium sulfate. Drying agent was filteredoff, solvent was evaporated to dryness and product was separated by LPCusing hexanes:ethyl acetate gradient (0-5% of AcOEt) as eluent.Fractions contained product were combined and evaporated to give pure4-O-benzyl-3-O-(2-ethyl)butyryl-6-O-tert-butyldimethylsilyl-2-deoxy-D-glucopyranose.

Yield 77%, [α]^(D)−0.22 (c=1.0, chloroform)

¹H NMR (CDCl₃, 300 MHz, 6) ppm: 7.35-7.27 (m, 5H, Haromat.), 6.41 (d,1H, J=6.0 Hz, H-1), 5.45-5.41 (m, 1H, H-3), 4.75 (dd, 1H, J=6 Hz, J=3Hz, H-2), 4.76 (d, 1H, J=11.2 Hz, CH₂Ph), 4.75 (dd, 1H, J=6 Hz, J=3 Hz,H-2), 4.70 (d, 1H, J=11.2 Hz, CH₂Ph), 3.98-3.93 (m, 2H, H-6, H-6′),3.92-3.84 (m, 2H, H-4, H-5), 2.24-2.17 (m, 1H, CHCO), 1.70-1.48 (m, 4H,2CH₂), 0.91 (s, 9H, tBu), 0.92-0.87 (m, 6H, 2CH₃), 0.08 (s, 6H, Me₂)

Synthesis of 4-O-Benzyl-3-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose

Solution of4-O-benzyl-3-O-(2-ethyl)butyryl-6-O-tert-butyldimethylsilyl-2-deoxy-D-glucopyranose(3.9 mmol) in THF (30 mL) was prepared and cooled down to 0° C.

Tetrabutylammonium fluoride (4.3 mmol) was added and the reactionmixture was stirred at room temp. After reaction was completed, thereaction mixture was diluted with water (60 mL) and extracted with ethylacetate (3×30 mL). Combined extracts were washed with water and driedover anhydrous sodium sulfate. Drying agent and solvent were removed andproduct was purified by LPC using hexanes:ethyl acetate gradient (0-10%of AcOEt) as eluents. Fractions contained product were pooled togetherto give pure 4-O-benzyl-3-O-(2-ethyl)butyryl-2-deoxy-D-glucopyranose(3.75 mmol, yield 96%).

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.38-7.27 (m, 5H, Harom.), 6.41 (dd, 1H,J=6 Hz, J=1.3 Hz, H-1), 5.48 (ddd, 1H, J=6.4 Hz, J=2.5 Hz, J=1.3 Hz,H-3), 4.80 (dd, 1H, J=6.1 Hz, J=2.6 Hz, H-2), 4.79 (d, 1H, J=11.3 Hz,CH₂Ph), 4.68 (d, 1H, J=11.3 Hz, CH₂Ph), 4.01-3.84 (m, 4H, H-4, H-5,H-6), 2.27-2.17 (m, 1H, CHCO), 1.73-1.46 (m, 4H, CH₂), 0.90 (t, 3H,J=7.4 Hz, CH₃), 0.90 (t, 3H, J=7.5 Hz, CH₃)

Synthesis of 4-O-Benzyl-3-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose

4-O-benzyl-3-O-(2-ethyl)butyryl-2-deoxy-D-glucopyranose (4.3 mmol) wasdissolved in THF (45 mL). 48% Water solution of HBr (1 mL, 9 mmol) wasadded and the reaction mixture was stirred at room temperature. After 30min., reaction was completed, and water (45 mL) was added. The mixturewas neutralized by addition of solid Na₂CO₃ (4.5 mmol, 477 mg). Obtainedsolution was extracted with ethyl acetate (3×40 mL). Combined organicextracts were washed with water, brine and dried over anhydrous sodiumsulfate. Solids and solvents were removed and crude product was purifiedby LPC using hexanes:ethyl acetate gradient (0-20% of AcOEt) forelution. Fractions contained product were pooled together and evaporatedto dryness to give pure 4-O-benzyl3-O-(2-ethyl)butyryl-2-deoxy-D-glucose (3.48 mmol, yield 81%), α:βratio=1.9:1

¹HNMR (DMSO-d6+D₃O, 300 MHz, δ) ppm: 7.34-7.25 (m, 5H, Harom.), 5.20(ddd, 1H, J=11.4 Hz, J=9.5 Hz, J=5 Hz, H-3α), 5.18 (d, 1H, J=3 Hz,H-1α), 4.95 (ddd, 1H, J=11.7 Hz, J=9.2 Hz, J=5.2 Hz, H-3β), 4.78 (dd,1H, J=10 Hz, J=2.2 Hz, H-1β), 4.63 (s, 2H, CH₂Ph α), 4.61 (s, 2H, CH₂Phβ), 3.76 (ddd, 1H, J=9.7 Hz, J=J=3.0 Hz, H-3α), 3.68-3.54 (m, 5H, H-5α,H-6α, H-6′α, H-6β, H-6′β), 3.54 (dd, 1H, J=9.4 Hz, H-4α), 3.35-3.33 (m,1H, H-5β), 2.20-1.98 (m, 4H, CHCOα, CHCOβ, H-2eα, H-2eβ), 1.58-1.34 (m,6H, H-2aα, H-2aβ, CH₂α, CH₂β), 0.83-0.75 (m, 6H, CH₃α, CH₃β)

Synthesis of 3-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose (WP1342)

Pd/C Degussa type (10%, contained 50% of water) (60 mg) was added to thesolution of 4-O-benzyl-3-O-(2-ethyl)butyryl-2-deoxy-D-glucopyranose (1.7mmol) in ethyl alcohol (70 mL). The mixture was hydrogenated using Paarapparatus with hydrogen (50 psi) for 24 hr. The reaction mixture wasthen filtered through Celite, evaporated to dryness, and product waspurified by LPC using chloroform:methanol gradient (0-20% of MeOH) forelution. Fractions contained product were pooled together and evaporatedto dryness to give pure 3-O-(2-ethyl)butyryl-2-deoxy-D-glucose (1.24mmol, yield 73%), α:β ratio=1.5:1

¹HNMR (DMSO-d6+D₂O, 300 MHz, δ) ppm: 5.14 (d, 1H, J=2.3 Hz, H-1α), 5.03(ddd, 1H, J=11.5 Hz, J=9.4 Hz, J=9.4 Hz, J=5.1 Hz, H-3α), 4.73 (ddd, 1H,J=11.9 Hz, J=8.6 Hz, J=5.2 Hz, H-3β), 4.69 (dd, 1H, J=10.2 Hz, J=1.5 Hz,H-1β), 3.65 (dd, 1H, J=10.7 Hz, J=1.9 Hz, H-6α), 3.63 (dd, 1H, J=10.0Hz, J=2.3 Hz, H-6β), 3.50 (dd, 1H, J=11.7 Jz, J=5.0 Hz, H-6′α),3.45-3.02 (m, 2H, H-5α, H-6′β), 3.28 (dd, 1H, J=J=9.5 Hz, H-4α), 3.18(dd, 1H, J=J=8.7 Hz, H-4β), 3.17-3.11 (m, 1H, H-5β), 2.19-2.06 (m, 2H,CHCOα, CHCOβ), 2.00 (ddd, 1H, J=12.0 Hz, J=5.2 Hz, J=1.7 Hz, H-2eβ),1.90 (dd, 1H, J=12.2 Hz, J=4.6 Hz, H-2eα), 1.58-1.38 (m, 5H, CH₂α,CH₂β), 1.32 (ddd, 1H, J=11.9 Hz, J=J=11.8 Hz, H-2aβ), 0.82 (t, 3H, J=7.3Hz, CH₃α), 0.90 (t, 3H, J=7.5 Hz, CH₃β)

Synthesis of 4-O-Valproyl-2-Deoxy-D-Glucopyranose (WP1513)

Synthesis of 3,6-Di-O-Benzyl-4-O-Valproyl-2-Deoxy-D-Glucopyranose

3,6-di-O-benzyl-2-deoxy-D-glucopyranose (3.4 g, 10.4 mmol) was dissolvedin DCM (15 mL). Pyridine (24.7 mmol, 2.0 mL) followed by valproylchloride (12 mmol, 1.9 mL) were added and obtained mixture was stirredat room temperature. After reaction was completed (TLC control), themixture was diluted with DCM (100 mL) and washed with water (2×40 mL),then with brine, and dried over anhydrous Na₂SO₄. Drying agent andsolvent were removed and product was purified by LPC using hexanes:ethylacetate gradient (0-10% of AcOEt) for elution. Fractions containedproduct were pooled together and evaporated to dryness to give 3.71 g(8.2 mmol) of pure product. Yield (85.3%)

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 7.34-7.26 (m, 5H, H arom.), 6.48 (dd,1H, J=6.3 Hz, J=0.8 Hz, H-1), 5.30 (dd, 1H, J=J=4.5 Hz, H-4), 4.89 (dd,1H, J=6.3 Hz, J=4.0 Hz, H-2), 4.60 (s, 2H, CH₂Ph), 4.58 (d, 1H, J=12.0Hz, CH₂Ph), 4.50 (d, 1H, J=12.0 Hz, CH₂Ph), 4.36-4.29 (m, 1H, H-5), 3.92(dd, 1H, J=J=4.0 Hz, H-3), 3.78 (dd, 1H, J=10.6 Hz, J=7.4 Hz, H-6), 3.66(dd, 1H, J=10.6 Hz, J=4.0 Hz, H-6), 2.45-2.32 (m, 1H, CHCO), 1.70-1.17(m, 8H, 4CH₂), 0.87 (t, 3H, J=7.2 Hz, CH₃), 0.85 (t, 3H, J=7.2 Hz, CH₃)

Synthesis of 3,6-Di-O-Benzyl-4-O-Valproyl-2-Deoxy-α-D-Glucopyranose

3,6-di-benzyl-4-O-valproyl-2-deoxy-D-glucopyranose (3 g, 6.6 mmol) wasdissolved in THF (30 mL). 48% HBr (water solution) (2 mL, 18 mmol) wasadded and the reaction mixture was stirred at room temperature. Afterreaction was completed (TLC control), the reaction mixture was dilutedwith water (15 mL). The mixture was neutralized by addition of solidNa₂CO₃ (9 mmol, 954 mg). THF was evaporated and ethyl acetate (100 mL)was added to the residue. Organic solution was washed with water, thenwith brine, and dried over anhydrous Na₂SO₄. Drying agent and solventwere removed and product was purified by LPC using hexanes:ethyl acetategradient (0-20% of AcOEt) for elution. Fractions contained product werepooled together and evaporated to dryness to give pure3,6-di-O-benzyl-4-O-valproyl-2-deoxy-α-D-glucopyranose 1.8 g (3.8 mmol)(yield 58%).

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 7.34-7.26 (m, 5H, H arom.), 5.42 (bs,1H, H-1), 4.93 (dd, 1H, J=9.8 Hz, J=9.3 Hz, H-4), 4.59 (d, 2H, J=12.1Hz, CH₂Ph), 4.50 (d, 1H, J=12.1 Hz, CH₂Ph), 4.48 (d, 1H, J=12.1 Hz,CH₂Ph), 4.16 (ddd. 1H, J=9.8 Hz, J=5.8 Hz, J=3.5 Hz, H-5), 4.00 (ddd,1H, J=11.2 Hz, J=9.1 Hz, J=4.9 Hz, H-3), 3.56-3.45 (m, 2H, H-6, H-6′),3.0 (bs, 1H, OH), 2.37-2.22 (m, 2H, H-2e, CHCO), 1.80-1.11 (m, 9H, H-2α,4CH₂), 0.80 (t, 3H, J=7.2 Hz, CH₃), 0.77 (t, 3H, J=7.2 Hz, CH₃)

4-O-Valproyl-2-Deoxy-D-Glucopyranose (WP1513)

Pd/C Degussa type (10% (50% wet)) (0.290 g) was added to the solution of3,6-di-O-benzyl-4-O-valproyl-2-deoxy-D-glucopyranose (1.5 g) in EtOH (20mL). Obtained mixture was hydrogenated at room temperature using Paarapparatus with hydrogen (50 psi). After 12 hr. reaction was completed,catalyst was filtered off and the solvent was evaporated to give a crudeproduct. Product was purified by LPC using CHCl₃: MeOH gradient (0-10%of MeOH) for elution. Fractions contained product were pooled together,evaporated to dryness and dried under reduced pressure, to give pure4-O-valproyl-2-deoxy-D-glucopyranose (0.64 g, yield 69%), α:β ratio=2:1

¹H NMR (DMSO-d6, δ) ppm: 5.14 (d, 1H, J=2.2 Hz, H-1α), 4.65 (d, 1H,J=7.9 Hz, H-1β), 4.53 (dd, 1H, J=J=9.6 Hz, H-4α), 4.44 (dd, 1H, J=J=9.8Hz, H-4β), 3.76 (ddd, 1H, J=12.1 Hz, J=9.6 Hz, J=5.0 Hz, H-3α), 3.70(ddd, 1H, J=9.8 Hz, J=5.7 Hz, J=2.2 Hz, H-5α), 3.55 (ddd, 1H, J=11.8 Hz,J=9.2 Hz, J=5.1 Hz, H-3β), 3.47-3.20 (m, 5H, H-6α, H-6′α, H-6β, H-6′β,H-5β), 2.37-2.24 (m, 2H, CHCOα, CHCOβ), 1.98 (dd, 1H, J=11.0 Hz, J=5.1Hz, H-2eβ), 1.86 (dd, 1H, J=12.1 Hz, J=5.2 Hz, H-2eα), 1.58-1.15 (m,18H, H-2aα, H-2aβ, 4CH₂α, 4CH₂β), 0.84 (t, 6H, J=7.0 Hz, CH₃), 0.83 (t,6H, J=7.9 Hz, CH₃)

Synthesis of 6-O-Acyl-2-Deoxy-D-Glucopyranose

Synthesis of 6-O-Acyl-3,4-Di-O-Benzyl-2-Deoxy-D-Glucopyranose

3,4-di-O-benzyl-2-deoxy-D-glucopyranose (2.76 mmol) and pyridine (5.52mmol), were dissolved in dichloromethane (20 mL). Obtained solution wascooled down to 0° C., and acyl chloride (3 mmol) was added. The mixturewas stirred at 0° C. After reaction was completed (TLC control), thereaction mixture was diluted with dichloromethane (30 mL), washed withwater (3×50 mL), and dried over anhydrous sodium sulfate. Drying agentand solvent were removed and product was purified by LPC usinghexanes:ethyl acetate gradient (0-10% of AcOEt) for elution. Fractionscontained product were pooled together and evaporated to dryness to givepure product. Following compounds were obtained according to thisprocedure: 3,4-Di-O-Benzyl-6-O-(2-Ethyl)Butyric-2-Deoxy-D-Glucopyranose

Yield 80%

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.37-7.22 (m, 10H, Harom.), 6.38 (dd, 1H,J=6.2 Hz, J=1.2 Hz, H-1), 4.90 (dd, 1H, J=6.2 Hz, J=2.7 Hz, H-2), 4.86(d, 1H, J=11.4 Hz, CH₂Ph), 4.66 (d, 2H, J=11.9 Hz, CH₂Ph), 4.56 (d, 1H,J=11.4 Hz, CH₂Ph), 4.50 (dd, 1H, J=12.1 Hz, J=2.7 Hz, H-6), 4.36 (dd,1H, J=12.1 Hz, J=5.4 Hz, H-6′), 4.22 (ddd, 1H, J=6 Hz, J=2.6 Hz, J=1.3Hz, H-3), 4.10 (ddd, 1H, J=8.2 Hz, J=5.4 Hz, J=2.6 Hz, H-5), 3.79 (dd,1H, J=8.5 Hz, J=6 Hz, H-4), 2.30-2.20 (m, 1H, CHCO), 1.72-1.45 (m, 4H,2CH₂), 0.89 (t, 6H, J=7.4 Hz, 2CH₃)

3,4-Di-O-Benzyl-6-O-Valproyl-2-Deoxy-D-Glucopyranose

Yield 76%

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.38-7.27 (m, 10H, Harom.), 6.38 (dd, 1H,J=6.2 Hz, J=1.2 Hz, H-1), 4.90 (dd, 1H, J=6.2 Hz, J=2.7 Hz, H-2), 4.86(d, 1H, J=11.4 Hz, CH₂Ph), 4.66 (d, 2H, J=11.9 Hz, CH₂Ph), 4.56 (d, 1H,J=11.4 Hz, CH₂Ph), 4.50 (dd, 1H, J=12.1 Hz, J=2.7 Hz, H-6), 4.36 (dd,1H, J=12.1 Hz, J=5.4 Hz, H-6′), 4.22 (ddd, 1H, J=6 Hz, J=2.6 Hz, J=1.3Hz, H-3), 4.10 (ddd, 1H, J=8.2 Hz, J=5.4 Hz, J=2.6 Hz, H-5), 3.79 (dd,1H, J=8.5 Hz, J=6 Hz, H-4), 2.30-2.20 (m, 1H, CHCO), 1.72-1.45 (m, 8H,4CH₂), 0.89 (t, 6H, J=7.4 Hz, 2CH₃)

Synthesis of 6-O-Acylo-3,4-Di-O-Benzyl-2-Deoxy-D-Glucopyranose

6-O-acylo-3,4-di-O-benzyl-2-deoxy-D-glucopyranose (1.1 mmol) wasdissolved in THF (10 mL). 48% Water solution of HBr (0.05 mL, 0.45 mmol)was added and the reaction mixture was stirred at room temperature.After reaction was completed (TLC control), the mixture was neutralizedby dilution with water (10 mL) and addition of solid Na₂CO₃ (0.225 mmol,24 mg). THF was evaporated and ethyl acetate (30 mL) was added to theresidue. Organic solution was washed with water, then with brine, anddried over anhydrous. Na₂SO₄. Solids and solvents were removed and crudeproduct was purified by LPC using hexanes:ethyl acetate gradient (0-20%of AcOEt) for elution. Fractions contained product were pooled togetherand evaporated to dryness to give pure product. Following compounds wereobtained according with this procedure:

3,4-Di-O-Benzyl-6-O-(2-Ethyl)Butyric-2-Deoxy-D-Glucopyranose

Yield 80% α:β ratio=3:1

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.40-7.28 (m, 10H, Harom.), 5.40 (bs, 1H,H-1a), 4.98 (d, 1H, J=10.8 Hz, CH₂Ph α), 4.97 (d, 2H, J=10.8 Hz, CH₂Phβ), 4.82 (m, 1H, H-1β), 4.74-4.60 (m, 6H, CH₂Phα, CH₂Phβ), 4.51 (dd, 1H,J=11.9 Hz, J=2.2 Hz, H-6α), 4.50 (dd, 1H, J=11.9 Hz, J=2.1 Hz, H-6β),4.30 (dd, 1H, J=11.9 Hz, J=4.2 Hz, H-6′α), 4.28 (dd, 1H, J=11.9 Hz,J=4.2 Hz, H-6′β), 4.09 (m, 2H, H-3α, H-5α), 3.72 (ddd, 1H, J=11.2 Hz,J=7.9 Hz, J=4.9 Hz, H-3β), 3.57-3.53 (m, 1H, H-5β), 3.52 (dd, 1H,J=J=9.0 Hz, H-4α), 3.47 (dd, 1H, J=J=9.0 Hz, H-4β), 3.14 (d, 1H, J=4.6Hz, OHβ), 2.58 (bs, 1H OHα), 2.44 (ddd, 1H, J=12.9 Hz, J=4.9 Hz, J=1.3Hz, H-2eβ), 2.34 (ddd, 1H, J=12.9 Hz, J=4.9 Hz, J=1.3 Hz, H-2eα),2.33-2.23 (m, 2H, CHCOα, CHCOβ), 1.74-1.45 (m, 10H, H-2aα, H-2α3, 2CH₂α,2CH₂β), 0.92 (t, 12H, J=7.4 Hz, 2CH₃α, 2CH₃β)

3,4-Di-O-Benzyl-6-O-Valproylo-2-Deoxy-D-Glucopyranose

Yield 75%, α:β ratio=3:1

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.40-7.28 (m, 10H, Harom.), 5.38 (bs, 1H,H-1a), 4.97 (d, 1H, J=10.8 Hz, CH₂Phα), 4.96 (d, 2H, J=10.8 Hz, CH₂Phβ),4.81 (d, 1H, J=8.9 Hz, H-1β), 4.74-4.58 (m, 3H, CH₂Phα, CH₂Phβ), 4.50(dd, 1H, J=12.1 Hz, J=1.9 Hz, H-6α), 4.48 (dd, 1H, J=11.9 Hz, J=2.1 Hz,H-6β), 4.30-4.20 (m, 2H, H-6′α, H-6′β), 4.09-4.00 (m, 2H, H-3α, H-5α),3.70 (ddd, 1H, J=12.4 Hz, J=7.8 Hz, J=5.3 Hz, H-3β), 3.57-3.47 (m, 1H,H-5β), 3.49 (dd, 1H, J=J=9.3 Hz, H-4α), 3.46 (dd, 1H, J=J=9.0 Hz, H-4β),2.53-2.36 (m, 3H, CHCOα, CHCOβ, H-2eβ), 2.32 (dd, 1H, J=13.0 Hz, J=5.0Hz, H-2eα), 1.72-1.22 (m, 18H, H-2aα, H-2α, 4CH₂α, 4CH₂β), 0.89 (t, 12H,J=7.2 Hz, 2CH₃α, 2CH₃β)

Synthesis of 6-O-Acylo-2-Deoxy-D-Glucopyranose

Pd/C Degussa type (10%, contained 50% of water) (40 mg) was added to thesolution of 6-O-acyl-3,4-di-O-benzyl-2-deoxy-D-glucopyranose (0.8 mmol)in ethyl alcohol (50 mL). The mixture was hydrogenated using Paarapparatus with hydrogen (35 psi) After reaction was completed (TLCcontrol), the reaction mixture was filtered through Celite, andevaporated to dryness. Product was purified by LPC usingchloroform:methanol gradient (0-10% of MeOH) for elution. Fractionscontained product were pooled together and evaporated to dryness to givepure product. Following compounds were obtained according with thisprocedure:

6-O-(2-Ethyl)Butyric-2-Deoxy-D-Glucopyranose (WP1319)

Yield 98.5%

¹HNMR (DMSO-d6+D₂O, 300 MHz, δ) ppm: 5.10 (d, 1H, J=2.5 Hz, H-1α), 4.63(dd, 1H, J=9.6 Hz, J=1.7 Hz, H-1β), 4.35 (dd, 1H, J=11.5 Hz, J=2.0 Hz,H-6α), 4.34 (dd, 1H, J=11.5 Hz, J=2.0 Hz, H-6β), 4.04 (dd, 1H, J=11.3Hz, J=5.3 Hz, H-6′α), 4.01 (dd, 1H, J=11.3 Hz, J=5.3 Hz, H-6′β), 3.73(ddd, 1H, J=9.6 HZ, J=5.3 Hz, J=2.0 Hz, H-5α), 3.67 (ddd, 1H, J=11.6 Hz,J=8.8 Hz, J=4.9 Hz, H-3α), 3.38 (ddd, 1H, J=12.1 Hz, J=8.6 HZ, J=5.0 Hz,H-3β), 3.26 (ddd, 1H, J=9.5 Hz, J=6.3 Hz, J=1.9 Hz, H-5β), 3.04 (dd, 1H,J=J=9.3 Hz, H-4α), 2.95 (dd, 1H, J=J=9.2 Hz, H-4β), 2.23-2.13 (m, 2H,CHCOα, CHCOβ), 1.92 (ddd, 1H, J=12.5 Hz, J=4.9 Hz, J=1.7 Hz, H-2eβ),1.80 (d, 1H, J=12 Hz, J=5.0 Hz, H-2eα), 1.60-1.38 (m, 9H, 2CH₂α, 4CH₂₄,H-2aα), 1.29 (ddd, 1H, J=10.0 Hz, J=J=12.1 Hz, H-2aβ), 0.84 (t, 12H,J=7.4 Hz, 2CH₃α, 2CH₃β)

6-O-Valproyl-2-Deoxy-D-Glucopyranose (WP1491)

Yield 80%, cα:β ratio=2.5:1

¹HNMR (DMSO-d6+D₂O, 300 MHz, δ) ppm: 5.05 (d, 1H, J=2.5 Hz, H-1α), 4.60(dd, 1H, J=9.7 Hz, J=1.7 Hz, H-1β), 4.33 (dd, 2H, J=11.6 Hz, J=1.8 Hz,H-6α, H-6β), 4.04-3.94 (m, 2H, H-6′α, H-6′β), 3.73-3.59 (m, 2H, H-3α,H-5α), 3.36 (ddd, 1H, J=11.5 Hz, J=8.5 Hz, J=5.0 Hz, H-3β), 3.22 (ddd,1H, J=9.3 Hz, J=6.2 Hz, J=1.2 Hz, H-5β), 3.02 (dd, 1H, J=J=9.3 Hz,H-4α), 2.93 (dd, 1H, J=J=9.1 Hz, H-4β), 2.35-2.23 (m, 2H, CHCOα, CHCOβ),1.90 (dd, 18H, J=10.7 Hz, J=5.0 Hz, H-2eβ, H-2eα, 4CH₂α, 4CH₂β), 0.82(t, 12H, J=7.2 Hz, 2CH₃α, 2CH₃β)

Synthesis of 1,3-Di-O-Acetyl-2-Deoxy-D-Glucopyranose

Synthesis of 4,6-Di-O-Benzyl-2-Deoxy-D-Glucopyranose

4,6-di-O-benzyl-2-deoxy-D-glucopyranose (4.9 mmol) was dissolved in THF(60 mL). 48% Water solution of HBr (0.4 mL, 3.6 mmol) was added and thereaction mixture was stirred at room temperature for 30 min.). Afterreaction was completed water (20 mL) followed by sodium carbonate (1.8mmol, 191 mg) were added and the mixture was stirred for additional 10min. The reaction mixture was extracted with ethyl acetate (3×40 mL).Combined organic extracts were washed with water until neutral and driedover sodium sulfate. Solids and solvents were removed and crude productwas purified by LPC using hexanes:ethyl acetate gradient (0-20% ofAcOEt) as eluents. Pure 4,6-di-O-benzyl-2-deoxy-D-glucose (3.1 mmol,yield 63%) was obtained.

Synthesis of 1,3-Di-O-Acyl-4,6-Di-O-Benzyl-2-Deoxy-D-Glucopyranose

4,6-Di-O-benzyl-2-deoxy-D-glucopyranose (3 mmol) was dissolved indichloromethane (30 mL). Pyridine (18 mmol) was added, and the reactionmixture was cooled down to 0° C. Appropriate acyl chloride (9 mmol) wasadded, and the reaction mixture was stirred at room temperature untilreaction was completed (TLC control), then reaction mixture was dilutedwith dichloromethane (70 mL), washed with water (3×50 mL) and dried overanhydrous sodium sulfate. Drying agent was filtered off, and solvent wasevaporated. Toluene (50 mL) was added to the residue, and evaporated todryness. Addition and evaporation of the toluene was repeated 3 times.Crude product was purified by LPC using hexanes:ethyl acetate gradient(0-10% of AcOEt) as eluents. Fractions contained product were pooledtogether and evaporated to dryness to give pure product. Followingcompounds were prepared according to this procedure1,3-Di-O-(2-Ethyl)Butyryl-4,6-Di-O-Benzyl-2-Deoxy-β-D-Glucopyranose

Yield 85%

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.39-7.18 (m, 10H, Harom.), 5.82 (dd, 1H,J=10.0 Hz, J=2.2 Hz, H-1), 5.07 (ddd, 1H, J=11.3 Hz, J=9.1 Hz, J=5.3 Hz,H-3), 4.74 (d, 1H, J=11 Hz, CH₂Ph), 4.65 (d, 1H, J=12.2 Hz, CH₂Ph), 4.57(d, 1H, J=11 Hz, CH₂Ph), 4.55 (d, 1H, J=12.2 Hz, CH₂Ph), 3.82-3.77 (m,2H, H-4, H-6), 3.74 (dd, 1H, J=11.0 Hz, J=2.0 Hz, H-6′), 3.60 (ddd, 1H,J=9.5 Hz, J=3.2 Hz, J=2.1 Hz, H-5), 2.43 (ddd, 1H, J=12.3 Hz, J=5.3 Hz,J=2.3 Hz, H-2e), 2.31-2.18 (m, 2H, CHCO), 1.77 (ddd, 1H, J=12.3 Hz,J=J=10 Hz, H-2α), 1.70-1.48 (m, 8H, 4CH₂), 0.99-0.87 (m, 6H, 2CH₃)

1,3-Di-O-Valproyl-4,6-Di-O-Benzyl-2-Deoxy-β-D-Glucopyranose

Yield 80%

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 7.35-7.14 (m, 10H, Harom.), 5.78 (dd, 1H,J=10.0 Hz, J=2.0 Hz, H-1), 5.04 (ddd, 1H, J=11.4 Hz, J=9.1 Hz, J=5.2 Hz,H-3), 4.72 (d, 1H, J=11 Hz, CH₂Ph), 4.63 (d, 1H, J=12.2 Hz, CH₂Ph), 4.56(d, 1H, J=11 Hz, CH₂Ph), 4.55 (d, 1H, J=12.2 Hz, CH₂Ph), 3.78 (dd, 1H,J=J=11.5 Hz, H-4), 3.77 (dd, 1H, J=11.2 Hz, J=3.6 Hz, H-6), 3.71 (dd,1H, J=11.2 Hz, J=1.9 Hz, H-6′), 3.58 (ddd, 1H, J=11.6 Hz, J=3.2 Hz,J=2.1 Hz, H-5), 2.45-2.30 (m, 3H, H-2e, 2CHCO), 1.80-1.51 (m, 5H, H-2α,2CH₂), 1.50-1.20 (m, 12H, 6CH₂), 0.95-0.78 (m, 12H, 4CH₃)

Synthesis of 1,3-Di-O-Acyl-2-Deoxy-D-Glucopyranose

Pd/C Degussa type (10%, contained 50% of water) was added to thesolution of 1,3-di-O-acyl-4,6-di-O-benzyl-2-deoxy-D-glucopyranose (1.7mmol) in ethyl alcohol (150 mL). The mixture was hydrogenated using Paarapparatus with hydrogen (50 psi) for 24 hr. The reaction mixture wasthen filtered through Celite, evaporated to dryness, and product waspurified by LPC using chloroform:methanol gradient (0-10% of MeOH) aseluent. Fractions contained product were pooled together and evaporatedto dryness to give pure product. Following compounds were synthesizedaccording to this procedure:

1,3-Di-O-(2-Ethyl)Butyryl-2-Deoxy-β-D-Glucopyranose (WP1261)

Yield 70%

¹HNMR (DMSO-d₆, 300 MHz, δ) ppm: 5.78 (dd, 1H, J=9.6 Hz, J=2.0 Hz, H-1),5.18 (d, 1H, J=10.9 Hz, OH), 4.87 (ddd, 1H, J=11.6 Hz, J=8.4 Hz, J=5.4Hz, H-3), 4.59 (dd, 1H, J=11.5 Hz, 6-OH), 3.67 (dd, 1H, J=10.7 Hz, J=5.6Hz, H-6), 3.53 (ddd, 1H, J=10.7 Hz, J=J=4.7 Hz, H-6′), 3.42-3.35 (m, 2H,H-4, H-5), 2.24 (m, 3H, CHCO, H-2e), 1.61-1.39 (m, 9H, 4CH₂, H-2α),0.87-0.80 (m, 6H, 2CH₃).

1,3-Di-O-Valproyl-2-Deoxy-β-D-Glucopyranose (WP1521)

Yield 70%

¹HNMR (CDCl₃, 300 MHz, δ) ppm: 5.81 (dd, 1H, J=9.9 Hz, J=1.2 Hz, H-1),4.92 (ddd, 1H, J=10.6 Hz, J=9.1 Hz, J=5.4 Hz, H-3), 3.92 (dd, 1H, J=11.7Hz, J=3.3 Hz, H-6), 3.83 (dd, 1H, J=11.7 Hz, J=4.3 Hz, H-6′), 3.68 (dd,1H, J=J=9.3 Hz, H-3), 3.47 (ddd, 1H, J=9.5 Hz, J=4.0 Hz, J=3.3 Hz, H-5),2.84 (bs, 1H, OH), 2.47-2.32 (m, 2H, 2CHCO), 2.28 (ddd, 1H, J=12.3 Hz,J=5.2 Hz, J=2.2 Hz, H-2e), 2.05 (bs, 1H, OH), 1.76 (dd, 1H, J=J=10.1 Hz,H-2α), 1.68-1.52 (m, 4H, 2CH₂), 1.50-1.21 (m, 12H, 6CH₂), 0.89 (t, 3H,J=7.2 Hz, CH₃), 0.88 (t, 3H, J=7.2 Hz, CH₃)

Synthesis of 1,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose

Synthesis of 3,4-Di-O-Benzyl-2-Deoxy-D-Glucopyranose

48% Hydrobromic acid (0.4 mL, 3.6 mmol) was added to the solution of3,4-di-O-benzyl-2-deoxy-D-glucopyranose (3.5 mmol) in THF (25 mL). Thereaction mixture was stirred at room temperature. After reaction wascompleted (TLC control), the reaction mixture was diluted with water (15mL). The mixture was neutralized by addition of solid Na₂CO₃ (1.8 mmol,191 mg). THF was evaporated and ethyl acetate (100 mL) was added to theresidue. Organic solution was washed with water, then with brine, anddried over anhydrous Na₂SO₄. Drying agent and solvent were removed andproduct was separated by LPC using hexanes:ethyl acetate gradient (0-10%of AcOEt) for elution. Fractions contained product were pooled togetherand evaporated to dryness to give3,4-di-O-benzyl-2-deoxy-D-glucopyranose (1.75 mmol, yield 50%).

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 7.39-7.30 (m, 10H, Harom.), 5.38 (d, 1H,J=2.4 Hz, H-1α), 4.97 (d, 1H, J=11.0 Hz, CH₂Ph α), 4.96 (d, 1H, J=11.0Hz, CH₂Ph β), 4.84 (d, 1H, J=8.4 Hz, H-1β), 4.74-4.62 (m, 3H, CH₂Phα,CH₂Phβ), 4.09 (ddd, 1H, J=11.3 Hz, J=8.8 Hz, J=4.9 Hz, H-3α), 3.95 (ddd,1H, J=9.6 Hz, J=4.8 Hz, J=2.8 Hz, H-5α), 3.90-3.81 (m, 2H, H-6α, H-6β),3.76-3.66 (m, 2H, H-6′α, H-6′β3), 3.49 (dd, 1H, J=J=9.6 Hz, H-4α), 3.48(dd, 1H, J=J=9.2 Hz, H-1β), 3.88 (ddd, 1H, J=9.3 Hz, J=4.8 Hz, J=2.6 Hz,H-5β), 3.10 (bs, 1H, OH), 2.41 (ddd, 1H, J=12.6 Hz, J=5.0 Hz, J=1.9 Hz,H-2eβ3), 2.32 (ddd, 1H, J=13.1 Hz, J=4.9 Hz, J=1.1 Hz, H-2eα), 1.67(ddd, 1H, J=13.1 Hz, J=11.5 Hz, J=4.5 Hz, H-2aα), 1.58 (ddd, 1H, J=12.6Hz, J=J=9.7 Hz, H-2aβ3)

Synthesis of1,6-Di-O-Acyl-3,4-Di-O-Benzyl-2-Deoxy-D-Glucopyranose—General Procedure

The mixture of 3,4-di-O-benzyl-2-deoxy-D-glucopyranose (1.6 mmol) andpyridine (9.6 mmol) in dichloromethane (20 mL) was prepared and cooleddown to 0° C. Acyl chloride (4.8 mmol) was added and the reactionmixture was stirred at room temperature. After reaction was completed,the reaction mixture was diluted with dichloromethane (80 mL) and washedwith water (3×30 mL), then dried over anhydrous sodium sulfate. Dryingagent and solvents were removed and product was separated by LPC withhexanes:ethyl acetate gradient (0-10% of AcOEt) for elution. Fractionscontained product were pooled together and evaporated to dryness.Following compounds were obtained according to this procedure:

1,6-Di-O-Butyryl-3,4-Di-O-Benzyl-2-Deoxy-D-Glucopyranose

Yield 70%, cc p ratio=1.2:1

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 7.38-7.28 (m, 10H, Harom.), 6.26 (d, 1H,J=1.9 Hz, H-1α), 5.723 (dd, 1H, J=10.0 Hz, J=2.3 Hz, H-1β), 4.97 (d, 1H,J=10.7 Hz, CH₂Ph α), 4.95 (d, 1H, J=10.7 Hz, CH₂Phβ), 4.74-4.60 (m, 3H,CH₂Phα, CH₂Phβ), 4.35-4.33 (m, 4H, H-6α, H-6′α, H-6β, H-6′β), 4.00 (ddd,1H, J=11.5 Hz, J=9.0 Hz, J=5.2 Hz, H-3α), 3.92 (ddd, 1H, J=10.0 Hz,J=J=3.5 Hz, H-5α), 3.78 (ddd, 1H, J=11.6 Hz, J=9.5 Hz, J=5.2 Hz, H-3β),3.62 (ddd, 1H, J=9.6 Hz, J=J=3.7 Hz, H-5β), 3.57 (dd, 1H, J=9.8 Hz,J=8.9 Hz, H-4α), 3.52 (dd, 1H, J=9.6 Hz, J=8.4 Hz, H-4β), 2.42-2.28 (m,6H, H-2eα, H-2eβ, and CH₂CO), 1.84 (ddd, 1H, J=13.8 Hz, J=11.5 Hz, J=3.5Hz, H-2α) 1.73-1.62 (m, 5H, H-2aα, and CH₂), 1.03-0.93 (m, 6H, CH₃)

1,6-Di-O-(2-Ethyl)Butyryl-3,4-Di-O-Benzyl-2-Deoxy-β-D-Glucopyranose

Yield 70%

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 7.38-7.28 (m, 10H, Harom.), 5.73 (dd,1H, J=9.9 Hz, J=2.2 Hz, H-1), 4.95 (d, 1H, J=10.8 Hz, CH₂Ph), 4.70 (d,1H, J=10.8 Hz, CH₂Ph), 4.62 (d, 1H, J=10.8 Hz, CH₂Ph), 4.61 (d, 1H,J=10.8 Hz, CH₂Ph), 4.45 (dd, 1H, J=11.9 Hz, J=2.2 Hz, H-6), 4.25 (dd,1H, J=11.9 Hz, J=5.0 Hz, H-6′), 3.76 (ddd, 1H, J=11.1 Hz, J=8.4 Hz,J=5.0 Hz, H-3), 3.60 (ddd, 1H, J=9.6 Hz, J=5.1 Hz, J=2.2 Hz, H-5), 3.50(dd, 1H, J=9.6 Hz, J=8.5 Hz, H-4), 2.36 (ddd, 1H, J=12.4 Hz, J=4.8 Hz,J=2.1 Hz, H-2e), 2.29-2.17 (m, 2H, CHCO), 1.72 (ddd, 1H, J=11.6 Hz,J=J=10.2 Hz, H-2α) 1.66-1.43 (m, 8H, CH₂), 0.97-0.85 (m, 12H, CH₃)

1,6-Di-O-Valproyl-3,4-Di-O-Benzyl-2-Deoxy-β-D-Glucopyranose

Yield 70%

¹H NMR (CDCl₃, 500 MHz, δ) ppm: 7.36-7.27 (m, 10H, Harom.), 5.71 (dd,1H, J=9.9 Hz, J=2.0 Hz, H-1), 4.94 (d, 1H, J=10.8 Hz, CH₂Ph), 4.70 (d,1H, J=11.5 Hz, CH₂Ph), 4.68 (d, 1H, J=11.0 Hz, CH₂Ph), 4.64 (d, 1H,J=11.5 Hz, CH₂Ph), 4.47 (dd, 1H, J=11.9 Hz, J=1.9 Hz, H-6), 4.21 (dd,1H, J=11.9 Hz, J=4.8 Hz, H-6′), 3.75 (ddd, 1H, J=11.5 Hz, J=8.5 Hz,J=4.9 Hz, H-3), 3.60 (ddd, 1H, J=9.5 Hz, J=4.6 Hz, J=1.9 Hz, H-5), 3.50(dd, 1H, J=9.8 Hz, J=9.3 Hz, H-4), 2.45-2.32 (m, 3H, H-2e, 2CHCO), 1.75(dd, 1H, J=J=11.6 Hz, H-2α), 1.66-1.56 (m, 4H, 2CH₂), 1.47-1.36 (m, 4H,2CH₂), 1.35-1.24 (m, 8H, 4CH₂), 0.91-0.85 (m, 12H, 4CH₃)

Synthesis of 1,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose—General Procedure

Pd/C Degussa type (10%, containing 50% of water) (100 mg) was added tothe solution of 1,6-di-O-acyl-3,4-di-O-benzyl-2-deoxy-D-glucopyranose (1mmol) in 95% anhydrous ethanol (100 mL). Obtained mixture washydrogenated at room temperature using Paar apparatus with hydrogen (45psi). After 24 hr. reaction was completed, catalyst was filtered off,and the solvent was evaporated to give a crude product. Product waspurified by LPC, using chloroform:methanol gradient (0-10% of MeOH) aseluent.

Fractions contained product were pooled together, evaporated to drynessand dried under reduced pressure. Following compounds were preparedaccording to this procedure: 1,6-Di-O-Butyryl-2-Deoxy-D-Glucopyranose(WP1217)

Yield (94%), α:β ratio=1.28:1

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 6.27 (d, 1H, J=2.2 Hz, H-1α), 5.78 (dd,1H, J=10.2 Hz, J=2.3 Hz, H-1β), 4.72 (dd, 1H, J=12.5 Hz, J=3.1 Hz,H-6α), 4.71 (dd, 1H, J=12.5 Hz, J=3.4 Hz, H-6β), 4.18 (dd, 1H, J=12.5Hz, J=2.2 Hz, H-6β), 4.18 (dd, 1H, J=12.5 Hz, J=2.2 Hz, H-6′α), 4.02(ddd, 1H, J=11.6 Hz, J=9 Hz, J=5 Hz, H-3α), 3.82-3.74 (m, 2H, H-5α,H-3β), 3.48 (ddd, 1H, J=9.7 Hz, J=3.2 Hz, J=2.2 Hz, H-5β), 3.42 (bs, 1H,OH), 3.24 (dd, 1H, J=J=9.3 Hz, H-4α), 3.19 (dd, 1H, J=J=9.3 Hz, H-4β),2.6 (bs, 1H, OH), 2.44-2.31 (m, 4H, CH₂), 2.25 (ddd, 1H, J=12.4 Hz,J=5.0 Hz, J=2.2 Hz, H-2eβ), 2.19 (ddd, 1H, J=13.7 Hz, J=5.0 Hz, J=1.4Hz, H-2e a), 1.81 (ddd, 1H, J=13.7 Hz, J=11.8 Hz, J=3.6 Hz, H-2aα), 1.72(ddd, 1H, J=J=12.0 Hz, J=10.2 Hz, H-2α), 1.69-1.63 (m, 4H, CH₂), 0.98(t, 3H, J=7.4 Hz, CH₃), 0.97 (t, 3H, J=7.3 Hz, CH₃)

1,6-Di-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose (WP1262)

Yield (78%), α:β ratio=1.1:1

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 6.29 (d, 1H, J=2.6 Hz, H-1α), 5.78 (dd,1H, J=10.1 Hz, J=2.2 Hz, H-1β), 4.69 (dd, 1H, J=12.4 Hz, J=3.4 Hz,H-6α), 4.61 (dd, 1H, J=12.3 Hz, J=3.8 Hz, H-6α), 4.24 (dd, 1H, J=12.3Hz, J=2.3 Hz, H-6′β), 4.12 (dd, 1H, J=12.4 Hz, J=2.2 Hz, H-6′α), 4.01ppm (ddd, 1H, J=11.5 Hz, J=8.9 Hz, J=5.0 Hz, H-3α), 3.80-3.71 (m, 2H,H-3β, H-5α), 3.49 (bs, 1H, OH), 3.47 (ddd, 1H, J=11.7 Hz, J=3.8 Hz,J=2.4 Hz, H-5β), 3.38 (bs, 1H, OH), 3.23 (dd, 1H, J=J=9.5 Hz, H-4α),3.20 (dd, 1H, J=J=9.1 Hz, H-4β), 2.69 (bs, 2H, OH), 2.35-2.20 (m, 3H,H-2eβ, CHCO), 2.17 (ddd, 1H, J=13.4 Hz, J=5.1 Hz, J=1.3 Hz, H-2eα), 1.81(ddd, 1H, J=13.6 Hz, J=11.7 Hz, J=3.6 Hz, H-2aα), 1.73-1.50 (m, 9H, CH₂and H-2aβ), 0.94-0.87 (m, 12H, CH₃)

1,6-Di-O-Valproyl-2-Deoxy-D-Glucopyranose (WP1489)

Yield (78%), α:β ratio=1:4

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 6.27 (d, 1H, J=2.7 Hz, H-1α), 5.75 (dd,1H, J=10.0 Hz, J=2.0 Hz, H-1β), 4.71 (dd, 1H, J=12.5 Hz, J=2.9 Hz,H-6α),4.60 (dd, 1H, J=12.4 Hz, J=3.4 Hz, H-6β), 4.21 (dd, 1H, J=12.4 Hz,J=2.2 Hz, H-6β), 4.05 (dd, 1H, J=12.5 Hz, J=2.0 Hz, H-6α), 4.03 (m, 1H,H-3α),3.70-3.77 (m, 2H, H-3β, H-5α), 3.05 (bs, 1H, OHα), 3.43 (ddd, 1H,J=9.6 Hz, J=J=2.8 Hz, H-5α), 3.29 (bs, 1H, OHβ), 3.19 (dd, 1H, J=J=9.7Hz, H-4α), 3.18 (dd, 1H, J=J=9.0 Hz, H-4β), 2.64 (bs, 1H, OHβ),2.50-2.34 (m, 4H, CHCOα, CHCOβ), 2.22 (ddd, 1H, J=12.4 Hz, J=4.7 Hz,J=2.0 Hz, H-2aβ), 2.15 (ss, 1H, J=12.3 Hz, J=4.4 Hz, H-2eα), 1.81-1.74(m, 1H, H-1aα), 1.71-1.55 (m, 9H, H-2α, 4CH₂α, 4CH₂β), 1.49-1.38 (m, 8H,4CH₂α, 4CH₂β), 1.36-1.25 (m, 24H, 4CH₃α, 4CH₃β)

Synthesis of 3,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose

3,6-Di-O-Acyl-4-O-Benzyl-2-Deoxy-D-Glucopyranoses—General Procedure

Solution of 4-O-benzyl-2-deoxy-D-glucopyranose (10 mmol) in a mixture ofmethylene chloride (30 mL) and pyridine (40 mmol) was prepared, andcooled down to 0° C. Acyl chloride (22 mmol) was slowly added and themixture was stirred at room temperature overnight. The reaction mixturewas diluted with DCM (50 mL) then washed with water (2×30 mL) and driedover anhydrous sodium sulfate. Drying agent and solvents were removedand product was purified by LPC using hexanes:ethyl acetate gradient(0-10% of AcOEt) for elution. Fractions contained product were pooledtogether, evaporated to dryness and dried under reduced pressure.Following compounds were prepared according to this procedure:4-O-Benzyl-3,6-Di-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose

¹H NMR (CDCl₃, δ) ppm: 7.36-7.29 (m, 5H, Harom.), 6.42 (dd, 1H, J=6.1Hz, J=1.2 Hz, H-1), 5.44 (dddd, 1H, J=0.7 Hz, J=1.4 Hz, J=3.2 Hz, J=5.4Hz, H-3), 4.83 (dd, 1H, J=6.1 Hz, J=3.2 Hz, H-2), 4.78 (d, 1H, J=11.2Hz, 1H, CH₂Ph), 4.63 (d, 1H, J=11.2 Hz, 1H, CH₂Ph), 4.43 (dd, 1H, J=3.4Hz, J=12.0 Hz, H-6), 4.37 (dd, 1H, J=5.4 Hz, J=12.0 Hz, H-6′), 4.19(ddd, 1H, J=8.2 Hz, J=3.4 Hz, J=5.5 Hz, H-5), 3.82 (dd, 1H, J=5.7 Hz,J=7.7 Hz, H-4), 2.31-2.18 (m, 2H, 2CH), 1.71-1.50 (m, 8H, 4CH₂),0.97-0.88 (m, 12H, 4CH₃).

4-O-Benzyl-3,6-Di-O-Valeroyl-2-Deoxy-D-Glucopyranose

¹H NMR (CDCl₃ 6), ppm: 7.40-7.31 (m, 5H, Harom.), 6.44 (dd, 1H, J=6.1Hz, J=1.2 Hz, H-1), 5.45 (dddd, 1H, J=0.6 Hz, J=1.3 Hz, J=3.2 Hz, J=5.7Hz, H-3), 4.83 (dd, 1H, J=6.1 Hz, J=3.1 Hz, H-2), 4.76 (d, 1H, J=11.5Hz, 1H, CH₂Ph), 4.66 (d, 1H, J=11.5 Hz, CH₂Ph), 4.42 (dd, 1H, J=3.4 Hz,J=12.0 Hz, H-6), 4.36 (dd, 1H, J=5.3 Hz, J=12.0 Hz, H-6′), 4.20 (ddd,1H, J=8.2 Hz, J=3.5 Hz, J=5.3 Hz, H-5), 3.83 (dd, 1H, J=5.7 Hz, J=7.9Hz, H-4), 2.38-2.28 (m, 4H, 2CH₂), 1.68-1.58 (m, 4H, 2CH₂), 1.44-1.31(m, 4H, 2CH₂), 0.94 (t, J=7.3 Hz, 3H, CH₃), 0.93 (t, J=7.3 Hz, 3H, CH₃).

4-O-Benzyl-3,6-Di-O-Butyryl-2-Deoxy-D-Glucopyranose

¹H NMR (CDCl₃, 8), ppm: 7.40-7.30 (m, 5H, Harom.), 6.44 (dd, 1H, J=6.1Hz, J=1.2 Hz, H-1), 5.45 (dddd, 1H, J=0.7 Hz, J=1.3 Hz, J=3.1 Hz, J=5.7Hz, H-3), 4.83 (dd, 1H, J=6.1 Hz, J=3.1 Hz, H-2), 4.76 (d, 1H, J=11.5Hz, 1H, CH₂Ph), 4.66 (d, 1H, J=11.5 Hz, CH₂Ph), 4.42 (dd, 1H, J=3.4 Hz,J=12.0 Hz, H-6), 4.37 (dd, 1H, J=5.3 Hz, J=12.0 Hz, H-6′), 4.20 (ddd,1H, J=8.3 Hz, J=3.4 Hz, J=5.3 Hz, H-5), 3.83 (dd, 1H, J=5.7 Hz, J=7.9Hz, H-4), 2.36-2.26 (m, 4H, 2CH₂), 1.5 (sext, 4H J=7.4 Hz, 2CH₂), 0.98(t, 6H, J=7.4 Hz, 2CH₃).

4-O-Benzyl-3,6-Di-O-Isovaleroyl-2-Deoxy-D-Glucopyranose

¹H NMR (CDCl₃, δ), ppm: 7.37-7.29 (m, 5H, Harom.), 6.42 (dd, 1H, J=6.1Hz, J=1.2 Hz, H-1), 5.43 (dddd, 1H, J=0.7 Hz, J=1.3 Hz, J=3.2 Hz, J=5.7Hz, H-3), 4.83 (dd, 1H, J=6.1 Hz, J=3.1 Hz, H-2), 4.74 (d, 1H, J=11.5Hz, 1H, CH₂Ph), 4.66 (d, 1H, J=11.5 Hz, CH₂Ph), 4.42 (dd, 1H, J=3.4 Hz,J=12.0 Hz, H-6), 4.34 (dd, 1H, J=5.4 Hz, J=12.0 Hz, H-6′), 4.17 (ddd,1H, J=8.2 Hz, J=3.4 Hz, J=5.4 Hz, H-5), 3.81 (dd, 1H, J=5.7 Hz, J=7.9Hz, H-4), 2.17 (d, 4H, J=12.1 Hz, 2CH₂), 2.11 (m, 2H, 2CHCO), 0.97 (t,3H, J=6.4 Hz, CH₃).

4-O-Benzyl-3,6-Di-O-Valproyl-2-Deoxy-D-Glucopyranose

¹H NMR (CDCl₃, δ), ppm: 7.37-7.27 (m, 5H, Harom.), 6.41 (dd, 1H, J=6.1Hz, J=1.1 Hz, H-1), 5.43 (m, 1H, H-3), 4.82 (dd, 1H, J=6.1 Hz, J=3.1 Hz,H-2), 4.77 (d, 1H, J=11.4 Hz, 1H, CH₂Ph), 4.63 (d, 1H, J=11.2 Hz, 1H,CH₂Ph), 4.43 (dd, 1H, J=3.0 Hz, J=12.1 Hz, H-6), 4.35 (dd, 1H, J=5.5 Hz,J=12.1 Hz, H-6′), 4.17 (ddd, 1H, J=8.1 Hz, J=3.0 Hz, J=5.5 Hz, H-5),3.81 (dd, 1H, J=5.8 Hz, J=7.9 Hz, H-4), 2.48-2.33 (m, 2H, CHCO), 1.7-1.2(m, 16H, 8 CH₂), 0.93-0.84 (m, 12H, 4 CH₃)

4-O-Benzyl-3,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose—General Procedure

47% Hydrobromic acid water solution (0.5 mL, 4.5 mmol) was added to amixture of 4-O-benzyl-3,6-di-O-acyl-2-deoxy-D-glucopyranose (5 mmol) intetrahydrofuran (50 mL), and obtained solution was stirred in roomtemperature. After reaction was completed water (20 mL) followed bysodium carbonate (2.25 mmol, 239 mg) were added and the mixture wasstirred for additional 10 min. The reaction mixture was extracted withethyl acetate (3×30 mL). Combined organic extracts were washed withwater until neutral and dried over sodium sulfate. Drying agent andsolvents were removed and product was purified by LPC usinghexanes:ethyl acetate gradient (0-30% of AcOEt) for elution. Fractionscontained product were pooled together, evaporated to dryness and driedunder reduced pressure. Following compounds were prepared according tothis procedure:

4-O-Benzyl-3,6-Di-O-Butyryl-α-D-Glucopyranose

Yield 63%

¹H NMR (CDCl₃, δ), ppm: 7.39-7.29 (m, 5H, Harom.), 5.44 (ddd, 1H, J=11.1Hz, J=8.9 Hz, J=5.1 Hz, H-3), 5.38 (m, 1H, H-1), 4.74 (d, 1H, J=11.2 Hz,CH₂Ph), 4.60 (d, 1H, J=11.2 Hz, CH₂Ph), 4.39 (dd, 1H, J=2.3 Hz, J=11.9Hz, H-6), 4.30 (dd, 1H, J=4.3 Hz, J=11.9 Hz, H-6′), 4.17 (ddd, 1H, J=9.8Hz, J=2.2 Hz, J=4.3 Hz, H-5), 3.55 (dd, 1H, J=J=9.5 Hz, H-4), 2.67 (dd,1H, J=2.1 Hz, J=3.2 Hz, OH), 2.30 (m, 5H, 2CH₂, H-2e), 1.68 (m, 5H,2CH₂, H-2α), 0.98 (t, 3H, J=7.3 Hz, CH₃), 0.96 (t, 3H, J=7.3 Hz, CH₃)

4-O-Benzyl-3,6-Di-O-Isovaleroyl-D-Glucopyranose

Yield 53%, α:β ratio=10:3

¹H NMR (CDCl₃, δ), ppm: 7.37-7.25 (m, 10H, Harom.), 5.40 (ddd, 1H,J=11.4 Hz, J=8.6 Hz, J=5.1 Hz, H-3α), 5.36 (m, 1H, H-1α), 5.05 (ddd, 1H,J=11.2 Hz, J=8.9 Hz, J=4.9 Hz, H-3β), 4.93 (m, 1H, H-1β), 4.73 (d, 1H,J=11.1 Hz, CH₂Phα), 4.71 (d, 1H, J=11.0 Hz, CH₂Ph β), 4.58 (d, 1H,J=11.1 Hz, CH₂Phα), 4.57 (d, 1H, J=11.0 Hz, CH₂Phβ), 4.41 (dd, 1H, J=2.0Hz, J=11.9 Hz, H-6β), 4.39 (dd, 1H, J=2.1 Hz, J=11.9 Hz, H-6α), 4.26(dd, 1H, J=4.3 Hz, J=11.9 Hz, H-6′α), 4.25 (dd, 1H, J=4.8 Hz, J=11.9 Hz,H-6′β), 4.14 (ddd, 1H, J=9.8 Hz, J=2.1 Hz, J=4.3 Hz, H-5α), 3.59 (m, 1H,H-5β), 3.54 (dd, 1H, J=J=9.5 Hz, H-4α), 3.53 (dd, 1H, J=J=9.5 Hz, H-4β),3.12 (m, 1H, OHβ), 2.62 (m, 1H, OHc), 2.45 (ddd, 1H, J=12.3, Hz, J=5.2Hz, J=2.4 Hz, H-2eβ), 2.32 (ddd, 1H, J=12.8 Hz, J=5.2 Hz, J=1.6 Hz,H-2eα), 2.23 (m, 4H, 2CHCOα, 2CHCOβ), 2.18-2.04 (m, 8H, 2CH₂α, 2CH₂₄),1.68 (ddd, 1H, J=J=12.5 Hz, J=3.5 Hz, H-2aα),1.56 (ddd, 1H, J=J=11.8 Hz,J=9.7 Hz, H-2aβ), 0.95 (t, 24H, J=6.8 Hz, 4CH₃α, 4CH₃β).

4-O-Benzyl-3,6-Di-O-Valeroyl-D-Glucopyranose

Yield 84%, α:β ratio=3:1

¹H NMR (CDCl₃, δ), ppm: 7.38-7.26 (m, 10H, Harom□), 5.42 (ddd, 1H,J=11.2 Hz, J=9.0 Hz, J=5.1 Hz, H-3α), 5.38 (m, 1H, H-1α), 5.06 (ddd, 1H,J=11.7 Hz, J=8.5 Hz, J=5.2 Hz, H-3β), 4.94 (m, 1H, H-1β), 4.73 (d, 1H,J=11.2 Hz, CH₂Phα), 4.71 (d, 1H, J=11.1 Hz, CH₂Ph), 4.61 (d, 1H, J=11.2Hz, CH₂Phα), 4.59 (d, 1H, J=11.1 Hz, CH₂Phβ), 4.41 (dd, 1H, J=2.0 Hz,J=11.9 Hz, H-6β), 4.39 (dd, 1H, J=2.3 Hz, J=11.9 Hz, H-6α), 4.29 (dd,1H, J=4.4 Hz, J=11.9 Hz, H-6′α), 4.27 (dd, 1H, J=4.7 Hz, J=11.9 Hz,H-6′β), 4.16 (ddd, 1H, J=9.8 Hz, J=2.3 Hz, J=4.3 Hz, H-5α), 3.61 (ddd,1H, J=9.7 Hz, J=2.1 Hz, J=4.7 Hz, H-5β), 3.55 (dd, 1H, J=J=9.4 Hz,H-4α), 3.54 (dd, 1H, J=J=9.4 Hz, H-4β), 3.14 (d, 1H, J=5.8 Hz, OHβ),2.65 (m, 1H, OHα), 2.45 (ddd, 1H, J=12.5 Hz, J=5.2 Hz, J=2.0 Hz, H-2eβ),2.38-2.24 (m, 9H, 2CH₂α, 2CH₂β, H-2eα), 1.70 (dddd, 1H, J=J=13.1 Hz,J=3.6 Hz, J=1.8 Hz, H-2aα), 1.62 (m, 8H, 2CH₂α, 2CH₂β), 1.56 (ddd, 1H,J=J=11.6 Hz, J=9.4 Hz, H-2aβ), 1.36 (m, 8H, 2CH₂α, 2CH₂β), 0.96-0.88 (m,12H, 2CH₃α, 2CH₃β).

4-O-Benzyl-3,6-Di-O-(2-Ethyl)Butyryl-D-Glucopyranose

Yield 69%, α:β ratio=7:3

¹H NMR (CDCl₃, δ), ppm: 7.34-7.26 (m, 10H, Harom.), 5.40 (ddd, 1H,J=11.1 Hz, J=8.9 Hz, J=5.1 Hz, 1H, H-3α), 5.35 (m, 1H, H-1α), 5.06 (ddd,1H, J=11.8 Hz, J=8.2 Hz, J=5.0 Hz, H-3β), 4.92 (m, 1H, H-1β), 4.79 (d,1H, J=10.9 Hz, CH₂Phα), 4.77 (d, 1H, J=10.9 Hz, CH₂Phβ), 4.58 (d, 1H,J=10.9 Hz, CH₂Phα), 4.56 (d, 1H, J=10.9 Hz, CH₂Phβ), 4.48 (dd, 1H, J=2.1Hz, J=11.9 Hz, 1H, H-6α, H-6β), 4.26 (dd, 1H, J=4.3 Hz, J=11.9 Hz,H-6′α), 4.25 (dd, 1H, J=4.5 Hz, J=11.9 Hz, H-6′β), 4.15 (ddd, 1H, J=9.6Hz, J=2.1 Hz, J=4.4 Hz, H-5α), 3.57 (m, 1H, H-5β), 3.56 (dd, 1H, J=J=9.3Hz, H-4α), 3.55 (dd, 1H, J=J=9.6 Hz, H-4β), 3.20 (d, 1H, J=5.6 Hz, OHβ),2.71 (m, 1H, OHα), 2.48 (ddd, 1H, J=12.5, Hz, J=5.3 Hz, J=2.3 Hz,H-2eβ), 2.35 (ddd, 1H, J=12.9 Hz, J=5.1 Hz, J=1.7 Hz, H-2eα), 2.30-2.20(m, 4H, 2CHCOα, 2CHCOβ), 1.60 (m, 38H, H-2aα, H-2aβ, 4CH₂α, 4CH₂β),0.88-0.82 (m, 24H, 4CH₃α, 4CH₃).

4-O-Benzyl-3,6-Di-O-Valproyl-D-Glucopyranose

Yield 78%, α:β ratio=2.5:1

¹H NMR (CDCl₃, δ), ppm: 7.36-7.24 (m, 10H, Harom.), 5.39 (ddd, 1H,J=11.1 Hz, J=9.00 Hz, J=5.0 Hz, H-3α), 5.34 (bs, 1H, H-1α), 5.04 (ddd,1H, J=12.8 Hz, J=8.3 Hz, J=5.2 Hz, H-3β), 4.93 (m, 1H, H-1β), 4.80 (d,1H, J=11.0 Hz, CH₂Phα), 4.77 (d, 1H, J=10.9 Hz, CH₂Ph), 4.57 (d, 1H,J=11.0 Hz, CH₂Phα), 4.56 (d, 1H, J=10.9 Hz, CH₂Ph β), 4.48 (dd, 1H,J=2.1 Hz, J=11.9 Hz, 1H, H-6α, H-6β), 4.27-4.19 (m, 1H, H-6′α, H-6′β),4.14 (ddd, 1H, J=9.8 Hz, J=2.1 Hz, J=4.1 Hz, H-5α), 3.57 (m, 1H, H-5β),3.56 (dd, 1H, J=J=9.3 Hz, H-4α), 3.60-3.50 (m, 2H, H-4β, H-5β), 3.16 (d,1H, J=5.4 Hz, OHβ), 2.65 (bs, 1H, OHα), 2.52-2.30 (m, 6H, CHCO(CHCOβ,H-2eα, H-2eβ), 1.70-1.20 (m, 18H, H-2aα, H-2aβ, 4CH₂α, 4CH₂β), 0.94-0.79(m, 24H, 4CH₃α, 4CH₃β).

3,6-Di-O-Acyl-D-Glucopyranose—General Procedure

Pd/C Degussa type (10% (50% wet)) (0.4 g) was added to the solution of3,6-di-O-acyl-4-O-benzyl-D-glucopyranose (5 mmol) in ethanol (50 mL).Obtained mixture was hydrogenated at room temperature using Paarapparatus with hydrogen (45 psi). After reaction was completed (TLCcontrol), catalyst was filtered off and the solvent was evaporated togive a crude product. Product was purified by LPC using hexanes:ethylacetate gradient (0-40% of AcOEt) for elution. Fractions containedproduct were pooled together, evaporated to dryness and dried underreduced pressure. Following compounds were prepared according to thisprocedure: 3,6-Di-O-(2-Ethyl)Butyryl-D-Glucopyranose (WP 1234)

Yield 81%, α:β ratio=5:2, [α]^(D)+48°, (c=1.39, chloroform)

¹H NMR (DMSO-d6+D₂O, δ), ppm: 5.15 (d, 1H, J=2.3 Hz, H-1α), 5.06 (ddd,1H, J=11.5 Hz, J=9.0 Hz, J=5.0 Hz, H-3α), 4.77 (ddd, 1H, J=12.0 Hz,J=9.3 Hz, J=5.3 Hz, H-3β), 4.75 (m, 1H, H-1β), 4.36 (dd, 1H, J=1.9 Hz,J=11.7 Hz, H-6β, H-6α), 4.08 (dd, 1H, J=5.4 Hz, J=11.7 Hz, H-6′α), 4.06(dd, 1H, J=6.1 Hz, J=11.6 Hz, H-6′β), 3.88 (ddd, 1H, J=9.8 Hz, J=2.0 Hz,J=5.3 Hz, H-5α), 3.42 (m, 1H, H-5β), 3.30 (dd, 1H, J=J=9.6 Hz, H-4α),3.25 (dd, 1H, J=J=9.6 Hz, H-4β), 2.11-2.26 (m, 2H, CHCOα, CHCOβ), 2.18(m, 4H, 2CHα, 2CHβ), 2.04 (ddd, 1H, J=12.2, Hz, J=5.2 Hz, J=2.0 Hz,H-2eβ), 1.93 (ddd, 1H, J=12.3 Hz, J=5.0 Hz, J=1.1 Hz, H-2eα), 1.60-1.41(m, 17H, 4CH₂β, 4CH₂β, H-2aα), 1.36 (ddd, 1H, J=J=11.8 Hz, J=9.8 Hz,H-2α), 0.84 (m, 24H, 4CH₃α, 4CH₃β).

3,6-Di-O-Valeroyl-D-Glucopyranose (WP 1232)

Yield 32%, α:β ratio 4:1, [α]^(D)+60°, (c=1.18, chloroform)

¹H NMR (DMSO-d6+D₂O, 6) ppm: 5.12 (d, 1H, J=2.3 Hz, H-1α), 5.00 (ddd,1H, J=11.6 Hz, J=9.4 Hz, J=5.1 Hz, H-3α), 4.73 (dd, 1H, J=9.6 Hz, J=1.8Hz, H-1β), 4.72 (ddd, 1H, J=11.6 Hz, J=8.9 Hz, J=5.1 Hz, H-3β), 4.27(dd, 1H, J=1.9 Hz, J=11.9 Hz, H-6β), 4.24 (dd, 1H, J=2.0 Hz, J=11.7 Hz,H-6α), 4.07 (dd, 1H, J=5.5 Hz, J=11.7 Hz, H-6′α), 4.03 (dd, 1H, J=5.9Hz, J=11.9 Hz, H-6′3), 3.85 (ddd, 1H, J=9.7 Hz, J=1.9 Hz, J=5.4 Hz,H-5α), 3.40 (m, 1H, H-5β), 3.27 (dd, 1H, J=J=9.6 Hz, H-4α), 3.23 (dd,1H, J=J=9.4 Hz, H-4β), 2.26 (m, 8H, 2CH₂α, 2CH₂β), 2.00 (ddd, 1H,J=12.0, Hz, J=5.2 Hz, J=1.8 Hz, H-2eβ3), 1.90 (ddd, 1H, J=12.4 Hz, J=5.2Hz, J=0.8 Hz, H-2eα), 1.48 (m, 9H, 2CH₂α, 2CH₂p, H-2aα), 1.33 (ddd, 1H,J=J=12.0 Hz, J=10 Hz, H-2aβ3), 1.26 (m, 8H, 2CH₂α, 2CH₂β), 0.84 (t,J=7.4 Hz, 12H, 2CH₃α, 2CH₃β).

3,6-Di-O-Isovaleroyl-α-D-Glucopyranose (WP1263)

Yield 51%, [α]^(D)+57°, (c=1.20, chloroform)

¹H NMR (DMSO-d6, δ), ppm: 6.43 (dd, 1H, J=4.0 Hz, J=1.3 Hz, 1-OH), 5.26(d, 1H, J=6.6 Hz, 4-OH), 5.14 (m, 1H, H-1), 5.03 (ddd, 1H, J=11.6 Hz,J=9.4 Hz, J=5.0 Hz, H-3), 4.28 (dd, 1H, J=1.9 Hz, J=11.7 Hz, H-6), 4.06(dd, 1H, J=5.5 Hz, J=11.7 Hz, H-6′), 3.86 (ddd, 1H, J=9.8 Hz, J=1.8 Hz,J=5.4 Hz, H-5), 3.28 (ddd, 1H, J=J=9.5 Hz, J=6.5 Hz, H-4), 2.15 (m, 4H,2CH₂), 2.04-1.87 (m, 3H, 2CH₂, H-2e), 1.48 (dd, 1H, J=J=12.4 Hz, H-2α),0.89 (d, 6H, J=6.6 Hz, 2CH₃), 0.88 (d, 6H, J=6.6 Hz, 2CH₃).

3,6-Di-O-Butyryl-α-D-Glucopyranose (WP1213)

Yield 89%, [α]^(D)+660, (c=1.23, chloroform)

¹H NMR (DMSO-d6+D₂O, δ), ppm: 5.15 (d, 1H, J=2.0 Hz, H-1), 5.03 (ddd,1H, J=11.7 Hz, J=9.3 Hz, J=5.1 Hz, H-3), 4.27 (dd, 1H, J=2.0 Hz, J=11.7Hz, H-6), 4.09 (dd, 1H, J=5.6 Hz, J=11.7 Hz, H-6′), 3.87 (ddd, 1H, J=9.9Hz, J=1.9 Hz, J=5.7 Hz, H-5), 3.30 (dd, 1H, J=J=9.5 Hz, H-4), 2.27 (m,4H, 2CH₂), 1.93 (ddd, 1H, J=11.8, Hz, J=5.0 Hz, J=1.0 Hz, H-2e),1.60-1.46 (m, 5H, 2CH₂, H-2α), 0.89 (t, 3H, J=7.4 Hz, CH₃), 0.88 (t, 3H,J=7.4 Hz, CH₃).

3,6-Di-O-Valproyl-D-Glucopyranose (WP 1506)

Yield 84%,

¹H NMR (CDCl₃, δ), ppm: 5.39 (bs, 1H, H-1α), 5.24 (ddd, 1H, J=11.7 Hz,J=9.3 Hz, J=5.2 Hz, H-3α), 4.97-4.85 (m, 2H, H-1β, H-3β), 4.47 (dd, 1H,J=12.2 Hz, J=4.0 Hz, H-6β), 4.44 (dd, 1H, J=12.1 Hz, J=4.0 Hz, H-6α),4.39 (dd, 1H, J=12.1 Hz, J=2.5 Hz, H-6′α), 4.37 (dd, 1H, J=12.2 Hz,J=2.1 Hz, H-6′β), 4.04 (ddd, 1H, J=9.7 Hz, J=3.8 Hz, J=2.6 Hz, H-5α),3.53-3.39 (m, 3H, H-4α, H-4β, H-5β), 3.22 (d, 1H, J=5.7 Hz, OHβ), 2.97(d, 1H, J=4.7 Hz, OH), 2.89 (d, 1H, J=3.9 Hz, OHβ), 2.75 (dd, 1H,J=J=2.6 Hz, OH), 2.51-2.30 (m, 3H, CHCOα, CHCOβ, H-2eβ), 2.20 (ddd, 1H,J=12.9 Hz, J=5.2 Hz, J=1.0 Hz, H-2eα), 1.78-1.22 (m, 18H, H-2α, H-2aβ,4CH₂α, 4CH₂β), 0.90 (t, 24H, J=7.2 Hz, 4CH₃α, 4CH₃13).

Synthesis of 4.6-Di-O-Acyl-2-Deoxy-D-Glucopyranose

3-O-Tert-Butyldimethylsilyl-4,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose—GeneralProcedure

Solution of 3-O-tert-butyldimethylsilyl-2-deoxy-D-glucopyranose (10mmol) and pyridine (40 mmol) in DCM (30 mL) was prepared and cooled downto 0° C. Acyl chloride (22 mmol) was slowly added and obtained reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with dichloromethane (50 mL), washed with water (2×30 mL) anddried over anhydrous sodium sulfate. Drying agent and solvents wereremoved and product was purified by LPC using hexanes:ethyl acetategradient (0-20% of AcOEt) for elution. Fractions contained product werepooled together, evaporated to dryness and dried under reduced pressure.Following compounds were prepared according to this procedure:3-O-Tert-Butyldimethylsilyl-4,6-Di-O-Butyryl-2-Deoxy-D-Glucopyranose

Yield 70%, [α]²⁰=−19.49 (c=1, chloroform).

¹H NMR (CDCl₃, δ) ppm: 6.37 (d, J=6.2 Hz, J=1.1 Hz, 1H, H-1), 5.08 (m,1H, H-4), 4.78 (ddd, 1H, J=6.2 Hz, J=3.5 Hz, J=0.6 Hz, H-2), 4.43 (m,1H, H-6), 4.27-4.15 (m, 3H, H-3, H-5, H-6′), 2.34 (m, 4H, 2 CH₂), 1.68(m, 4H, 2 CH₂), 0.98 (t, J=7.4 Hz, 3H, CH₃), 0.97 (t, J=7.4 Hz, 3H,CH₃), 0.90 (s, 6H, t-Bu), 0.11, 0.10 (2s, 3H, Me₂Si)

3-O-Tert-Butyldimethylsilyl-4,6-Di-O-Valeroyl-2-Deoxy-D-Glucopyranose

Yield 85%, [α]²⁰=−21.69 (c=1, chloroform)

¹H NMR (CDCl₃, δ) ppm: 6.35 (d, J=6.2 Hz, J=1.0 Hz, 1H, H-1), 5.04 (m,1H, H-4), 4.76 (ddd, 1H, J=6.2 Hz, J=3.6 Hz, J=0.6 Hz, H-2), 4.41 (m,1H, H-6), 4.25-4.13 (m, 3H, H-3, H-5, H-6′), 2.34 (m, 4H, 2 CH₂), 1.61(m, 4H, 2 CH₂), 1.35 (m, 4H, 2 CH₂), 0.91 (t, J=7.4 Hz, 3H, CH₃), 0.91(t, J=7.4 Hz, 3H, CH₃), 0.88 (s, 9H, t-Bu), 0.09, 0.08 (2s, 3H ea,Me₂Si)3-O-tert-butyldimethylsilyl-4,6-di-O-(2-ethyl)butyryl-2-deoxy-D-glucopyranose

Yield 98%, [α]²⁰=−20.32 (c=1, chloroform)

¹H NMR (CDCl₃, δ) ppm: 6.35 (d, 1H, J=6.4 Hz, H-1), 5.02 (ddd, J=J=3.7Hz, J=1.1 Hz, 1H, H-4), 4.83 (ddd, 1H, J=6.1 Hz, J=4.5 Hz, J=1.2 Hz,H-2), 4.54 (dd, 1H, J=12.1 Hz, J=8.1 Hz, H-6), 4.34 (m, 1H, H-3), 4.24(dd, 1H, 1H, J=12.0 Hz, J=3.2 Hz, H-6′), 4.04 (m, 1H, H-5), 2.30 (m, 2H,2 CHCO), 1.65 (m, 8H, 4 CH₂), 0.91 (t, J=7.4 Hz, 12H, 4 CH₃), 0.13 (s,9H, t-Bu), 0.12, 0.08 (2s, 3H ea, Me₂Si), 0.08

3-O-Tert-Butyldimethylsilyl-4,6-Di-O-Valproyl-2-Deoxy-D-Glucopyranose

(Yield 79.7%)

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 6.36 (d, 1H, J=6.3 Hz, H-1), 4.96 (ddd,1H, J=3.5 Hz, J=3.5 Hz, J=1.1 HZ, H-4), 4.81 (ddd, 1H, J=6.0 Hz, J=4.5Hz, J=1.1 Hz, H-2), 4.51 (dd, 1H, J=12.0 Hz, J=8.2 Hz, H-6), 4.34-4.26(m, 1H, H-5), 4.20 (dd, 1H, J=12.0 Hz, J=3.2 Hz, H-6′), 3.96-4.02 (m,1H, H-3), 2.50-2.35 (m, 2H, CHCO), 1.73-1.23 (m, 16H, 8CH₂), 0.92 (t,6H, J=7.2 Hz, 2CH₃), 0.89 (t, 6H, J=7.2 Hz, 2CH₃), 0.89 (s, 9H, t-BuSi),0.11, 0.10 (2s, 3H ea, MeSi)

4,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose—General Procedure

Solution of4,6-di-O-acyl-3-tert-butyldimethylsilyl-2-deoxy-D-glucopyranose (5 mmol)in THF (50 mL) was prepared. 1M Solution of tetrabutylammonium fluoridein tetrahydrofurane (5 ml, 5 mmol) was added and the mixture was stirredin room temperature overnight. After reaction was completed the reactionmixture was poured into the water (150 mL), and water solution wasextracted with ethyl acetate (3×30 mL). Combined organic extracts werewashed with water until neutral and dried over anhydrous sodium sulfate.Drying agent and solvents were removed and product was purified by LPCusing hexanes:ethyl acetate gradient (0-30% of AcOEt) for elution.Fractions contained product were pooled together, evaporated to drynessand dried under reduced pressure. Following compounds were preparedaccording to this procedure:

4,6-Di-O-Butyryl-2-Deoxy-D-Glucopyranose

Yield 70%,

¹H NMR (CDCl₃, δ) ppm: 6.42 (dd, J=6.1 Hz, J=1.4 Hz, 1H, H-1), 4.99 (dd,J=6.4 Hz, J=9.0 Hz, 1H, H-4), 4.88 (dd, J=6.1 Hz, J=2.8 Hz, 1H, H-2),4.39 (dd, J=5.2 Hz, J=12.3 Hz, 1H, H-6), 4.33 (ddd, J=6.4 Hz, J=2.6 Hz,J=1.4 Hz, 1H, H-3), 4.30 (dd, J=2.6 Hz, J=12.3 Hz, 1H, H-6′), 4.14 (ddd,J=9.0 Hz, J=5.3 Hz, J=2.6 Hz, 1H, H-5), 2.65 (m, 1H, OH), 2.38 (t, J=7.4Hz, 2H, CH₂), 2.35 (t, J=7.4 Hz, 2H, CH₂), 1.69 (sext, J=7.4 Hz, 2H,CH₂), 1.67 (sext, J=7.4 Hz, 2H, CH₂), 0.98 (t, J=7.4 Hz, 3H, CH₃), 0.96(t, J=7.4 Hz, 3H, CH₃)

4,6-Di-O-Valeroyl-2-Deoxy-D-Glucopyranose

Yield 25%, [α]²⁰=43.72 (c=1, chloroform)

¹H NMR (CDCl₃, δ) ppm: 6.42 (dd, J=6.1 Hz, J=1.5 Hz, 1H, H-1), 4.99 (dd,J=6.3 Hz, J=9.0 Hz, 1H, H-4), 4.88 (dd, J=6.1 Hz, J=2.8 Hz, 1H, H-2),4.39 (dd, J=5.2 Hz, J=12.3 Hz, 1H, H-6), 4.33 (ddd, J=6.3 Hz, J=2.7 Hz,J=1.5 Hz, 1H, H-3), 4.30 (dd, J=2.6 Hz, J=12.3 Hz, 1H, H-6′), 4.14 (ddd,J=8.9 Hz, J=5.2 Hz, J=2.6 Hz, 1H, H-5), 2.65 (m, 1H, OH), 2.40 (t, J=7.4Hz, 2H, CH₂), 2.37 (t, J=7.4 Hz, 2H, CH₂), 1.70-1.58 (m, 4H, 2CH₂),1.44-1.32 (m, 4H, 2CH₂), 0.94 (t, J=7.3 Hz, 3H, CH₃), 0.93 (t, J=7.4 Hz,3H, CH₃).

4,6-Di-O-(2-Ethyl)Butyryl-2-Deoxy-D-Glucopyranose

Yield 45%, [α]²⁰=60.16 (c=1, chloroform)

¹H NMR (CDCl₃, δ) ppm: 6.39 (dd, 1H, J=6.1 Hz, J=1.4 Hz, H-1), 4.99 (dd,1H, J=6.2 Hz, J=8.9 Hz, H-4), 4.85 (dd, 1H, J=6.1 Hz, J=2.8 Hz, H-2),4.46 (dd, 1H, J=2.4 Hz, J=12.1 Hz, H-6), 4.3) (m, 1H, H-3), 4.23 (dd,1H, J=5.3 Hz, J=12.1 Hz, H-6′), 4.13 (ddd, 1H, J=8.6 Hz, J=5.3 Hz, J=2.4Hz, H-5), 2.80 (m, 1H, OH), 2.27 (m, 2H, 2CHCO), 1.70-1.45 (m, 8H,4CH₂), 0.95-0.85 (m, 12H, 4CH₃).4,6-Di-O-Valproyl-2-Deoxy-D-Glucopyranose

(Yield 93.8%)

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 6.40 (dd, 1H, J=6.0 Hz, J=1.3 Hz, H-1),4.97 (dd, 1H, J=8.9 Hz, J=6.2 Hz, H-4), 4.85 (dd, 1H, J=6.1 Hz, J=2.8Hz, H-2), 4.47 (dd, 1H, J=12.0 Hz, J=2.1 Hz, H-6), 4.30 (bs, 1H, H-3),4.24-4.09 (m, 2H, H-5, H-6′) 2.83 (bs, 1H, OH), 2.50-2.36 (m, 2H, CHCO),1.70-1.21 (m, 16H, 8CH₂), 0.95-0.85 (m, 12, 4CH₃)

4,6-Di-O-Acyl-2-Deoxy-D-Glucopyranose—General Procedure

47% Hydrobromic acid (0.5 mL) was added to a solution of4,6-di-O-acyl-2-deoxy-D-glucopyranose (5 mmol, 4.5 mmol) in THF (50 mL),and the mixture was stirred at room temperature. After reaction wascompleted water (25 mL) followed by sodium carbonate (2.25 mmol, 239 mg)were added and the mixture was stirred for additional 10 min. Thereaction mixture was extracted with ethyl acetate (3×30 mL). Combinedorganic extracts were washed with water until neutral and dried oversodium sulfate. Drying agent and solvents were removed and product waspurified by LPC using methylene chloride:methanol gradient (0-40% ofMeOH) for elution. Fractions contained product were pooled together,evaporated to dryness and dried under reduced pressure. Followingcompounds were prepared according to this procedure:

4,6-Di-O-Valeroyl-2-Deoxy-D-Glucopyranose (WP1233)

Yield 79%, α:β ratio=10:1, [α]^(D)+600, (c=1.39, chloroform)

¹H NMR (DMSO-d6+D₂O, 6) ppm: 5.15 (dd, 1H, J=2.4 Hz, H-1α), 4.70 (dd,1H, J=9.5 Hz, J=1.5 Hz, H-1β), 4.58 (dd, 1H, J=J=9.5 Hz, H-4α), 4.51(dd, 1H, J=J=9.5 Hz, H-4β), 4.00 (dd, 2H, J=12.1 Hz, J=5.1 Hz, H-6α,H-6β), 3.91 (m, 3H, H-6′α, H-6′β, H-5α), 3.83 (ddd, 1H, J=11.6 Hz, J=9.2Hz, J=5.0 Hz, H-3α), 3.61 (ddd, 1H, J=11.6 Hz, J=9.2 Hz, J=5.0 Hz,H-3β), 3.50 (m, 1H, H-5β), 2.28 (t, 4H, J=6.8 Hz, CH₂α(, CH₂), 2.24 (t,4H, J=7.4 Hz, CH₂α(, CH₂), 1.99 (ddd, 1H, J=12.4 Hz, J=5.2 Hz, J=1.9 Hz,H-2eβ), 1.88 (dd, 1H, J=12.2 Hz, J=5.2 Hz, H-2eα), 1.58-1.38 (m, 10H, 2CH₂α, 2 CH₂β, H-2aα, H-2aβ), 1.26 (m, 8H, 2 CH₂α, 2 CH₂β), 0.84 (t, 12H,J=7.5 Hz, 2CH₃α, 2CH₃).

4,6-Di-O-Butyryl-2-Deoxy-D-Glucopyranose (WP1214)

Yield 78%, α:β ratio=10:1, [α]^(D)+620, (c=1.36, chloroform)

¹H NMR (DMSO-d6+D₂O, 6) ppm: 5.18 (dd, 1H, J=2.4 Hz, H-1α), 4.72 (dd,1H, J=9.8 Hz, J=1.8 Hz, H-1β), 4.61 (dd, 1H, J=J=9.6 Hz, H-4α), 4.54(dd, 1H, J=J=9.5 Hz, 1H, H-4β), 4.04 (dd, 2H, J=12.1 Hz, J=5.0 Hz, H-6α,H-6β),3.99-3.89 (m, 3H, H-6′α, H-6′β, H-5α), 3.86 (ddd, 1H, J=11.6 Hz,J=9.3 Hz, J=5.0 Hz, H-3α), 3.63 (ddd, 1H, J=10.6 Hz, J=8.9 Hz, J=4.9 Hz,H-3β), 3.52 (m, 1H, H-5β), 2.33-2.22 (m, 8H, 2 CH₂α, 2 CH₂β), 2.02 (ddd,1H, J=12.3 Hz, J=5.2 Hz, J=2.1 Hz, H-2eβ), 1.91 (ddd, 1H, J=12.9 Hz,J=5.1 Hz, J=0.8 Hz, H-2eα), 1.54 (m, 9H, 2 CH₂α, 2 CH₂β, H-2aα), 1.49(ddd, 1H, J=J=12.0 Hz, J=10.0 Hz, H-2aβ), 0.89 (t, 6H, J=7.4 Hz, 6H,CH₃α, CH₃β), 0.99 (t, 6H, J=7.4 Hz, CH₃α, CH₃β).

4,6-Di-O-(2-Ethyl)Butyryl-2-Deoxy-α-D-Glucopyranose (WP1241)

Yield 78%, [α]^(D)+74°, (c=1.21, chloroform)

¹H NMR (DMSO-d6+D₂O, 6) ppm: 5.18 (dd, 1H, J=2.2 Hz, H-1), 4.61 (dd, 1H,J=J=9.4 Hz, H-4), 4.13 (d, 1H, J=11.3 Hz, H-6), 3.99-3.86 (m, 2H, H-6′,H-5), 3.85 (ddd, 1H, J=11.5 Hz, J=9.4 Hz, J=5.0 Hz, H-3α), 2.20 (m, 2H,2 CHCO), 1.91 (dd, 1H, J=12.8 Hz, J=5.1 Hz, H-2e), 1.52 (m, 9H, 4CH₂,H-2α), 0.84 (m, 12H, 4CH₃).

4.6-Di-O-Valproyl-2-Deoxy-D-Glucopyranose (WP1483)

(Yield %), α:β ratio=3:1

¹H NMR (CDCl₃, 300 MHz, δ) ppm: 5.39 (bs, 1H, H-1α), 4.92-4.85 (m, 1H,H-1β), 4.77 (dd, 1H, J=J=9.6 Hz, H-4α), 4.73 (dd, 1H, J=J=9.6 Hz, H-4β),4.41 (dd, 1H, J=12.0 Hz, J=2.0 Hz, H-6α), 4.37 (dd, 1H, J=12.1 Hz, J=2.0Hz, H-6β), 4.20-4.06 (m, H-3α, H-5α, H-6′β), 4.02 (dd, 1H, J=12.1 Hz,J=4.4 Hz, H-6′α), 3.87-3.74 (m, 1H, H-H-3β), 3.65 (ddd, 1H, J=9.0 Hz,J=5.4 Hz, J=2.2 Hz, H-5β), 3.22 (d, 1H, J=6.3 Hz, OH-β), 2.78 (d, 1H,J=5.3 Hz, OH-β), 2.62 (dd, 1H, J=2.9 Hz, J=2.3 Hz, OH-α), 2.50 (d, 1H,J=5.3 Hz, OH-α), 2.47-2.35 (m, 5H, CHCOα, CHCOβ, H-2eβ), 2.27 (ddd, 1H,J=13.6 Hz, J=5.2 Hz, J=1.0 Hz, H-2eα), 1.77-1.20 (m, 18H, H-2aα, H-2α,4CH₂α, 4CH₂β), 0.94-0.85 (m, 24H, 4CH₃α, 4CH₃β).

Activity

In the first set of assays, IC₅₀ values were determined for eachcompound after 72 hours of drug exposure in each of the tumor celllines. Cell lines tested include D54, U87, Panc-1, AsPc-1, Colo357-FG,L3.6, H226, H352, H441 cell lines.

U87 is a human primary glioblastoma cell line formally known as U-87 MG.It has epithelial morphology, and was obtained from a 44 years oldfemale patient with stage four cancer. U-87 MG can be obtained from theAmerican Type Culture Collection (ATCC) where it is known by theaccession number HTB-14. The entire sequence of the genome of U-87 MGhas recently been published in PLoS Genetics, 2010 January; 6(1):e1000832. This is a hypodiploid human cell line with the modalchromosome number of 44 occurring in 48% of cells. The rate of higherploidy was 5.9%. Twelve markers were common to all cells, includingder(1)t(1;3) (p22;q21), der(16)t(1;16) (p22;p12), del(9) (p13) and nineothers. The marker der(1) had two copies in most cells. There was onlyone copy of normal X. N1, N6 and N9 were not found.

COLO 357 FG is continuous human cell line, COLO 357, with exceptionalcharacteristics was derived from a metastasis of a pancreaticadenocarcinoma. COLO 357 grew as an adhering monolayer with a celldoubling time of 21 h and grew with 10% clonal efficiency in soft agar.COLO 357 cells had numerous lamellar inclusions. The cells elaboratedthe pancreatic enzymes trypsin, elastase and chymotrypsin. COLO 357 alsosecreted appreciable amounts of carcinoembryonic antigen and humanchorionic gonadotropin. COLO 357 had a chromosome mode of 53 with 20identifiable Giemsa-banded marker chromosomes. Nine nucleolar organizingregions were found by silver-stained metaphase preparations. COLO 357has been “fingerprinted” for seven allelic isozymes.

Panc-1 is a human pancreatic cancer cell line. It has epithelialmorphology and was obtained from a 56 years old male caucasian patient.Chromosome studies indicate a modal number of 63 with 3 distinct markerchromosomes and a small ring chromosome. This is a hypertriploid humancell line. The modal chromosome number was 61, occurring in 32% ofcells. However, cells with 63 chromosomes also occurred at a highfrequency (22%). The rate of cells with higher ploidies was 8.5%.

AsPc-1 cell line was derived from nude mouse xenografts initiated withcells from the ascites of a 62 years old female Caucasian patient withcancer of the pancreas.

L3.6 is a highly metastatic human pancreatic cancer cell line.

H226 is a squamous cell carcinoma cell line. The morphology of thedisease is epithelial and was collect from lung tissues (pleuraleffusion of a male patient with mesothelioma.

H441 is a human lung adenocarcinoma epithelial cell line.

All cell lines were maintained in respective growth media at 37° C., 5%CO₂ and 98% humidity. Cells were treated with the compounds and all drugconcentrations were diluted so that the final concentration of DMSO is0.5%. The cytotoxic effect was measured by the MTS Assay (Tetrazolium),which is a colorimetric method for determining the number of viablecells. After the 72 hours of incubation with drug, Promega's MTS reagentwere added to the cells according to manufacturer's instructions andincubated for 2 hours. The plates were read at 490 nm and the resultingdata graphed with GraphPad Prism 5 software.

IC₅₀ was calculated, which is approximate equivalent of IG₅₀(concentration at which 50% growth inhibition is measured). Theindividual IC₅₀ values (72 hours drug exposure) are shown in Table 1.The IC₅₀ values represent 100% of the drug concentration.

TABLE 1 Chemical Structures Of 2-Dg Esters And Their Vitro ActivityBrain Pancreatic Tumor Cancer No Structure U87 Colo357-FG WP1213

 0.24 mM 0.38 mM WP1214

 0.30 mM 0.44 Mm WP1216

 3.58 mM — WP1217

 2.33 mM — WP1231

 0.38 mM 0.55 mM WP1232

 0.25 mM 0.49 mM WP1233

 0.20 mM 0.23 mM WP1234

0.055 mM 0.10 mM WP1241

0.123 mM 0.28 mM WP1242

0.490 mM 6.38 mM WP1261

0.741 mM 0.34 mM WP1262

0.264 mM 0.21 mM WP1263

0.037 mM 0.16 mM WP1317

 2.10 mM  2.1 mM WP1319

 3.0 mM 1.70 mM WP1342

 2.4 mM 13.2 mM WP1343

0.109 mM 0.75 mM WP1357

— 0.54 mM WP1474

 2.4 mM — WP1490

 2.4 mM  2.0 mM WP1512

 0.74 mM — WP1513

 1.2 mM  1.2 mM WP1491

 2.1 mM — WP1489

WP1506

WP1483

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present invention. However, theinvention described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description, which do not depart from thespirit or scope of the present inventive discovery. Such modificationsare also intended to fall within the scope of the appended claims.

All references cited in this specification are hereby incorporated byreference. The discussion of the references herein is intended merely tosummarize the assertions made by their authors and no admission is madethat any reference constitutes prior art relevant to patentability.Applicant reserves the right to challenge the accuracy and pertinency ofthe cited references.

What is claimed is:
 1. A method of treating brain or pancreatic cancerin a patient in need thereof comprising administering a therapeuticallyeffective amount of one or more compounds of the Formula I:

or a salt thereof, wherein: each R¹, R², R³ and R⁴ are independently H,or C(O)R⁵; at least two of R¹, R², R³ and R⁴ is C(O)R⁵; and each R⁵ isindependently selected from C₃-C₇ straight- or branched-chain alkyl,C₄-C₁₀ alkylcycloalkyl, and C₃-C₇ cycloalkyl.
 2. The method of claim 1,wherein R² and R³ are C(O)R⁵.
 3. The method of claim 1, wherein thecompound is chosen from:


4. A method of treating brain or pancreatic cancer in a patient in needthereof comprising administering a therapeutically effective amount ofthe compound


5. A method of treating brain or pancreatic cancer in a patient in needthereof comprising administering a therapeutically effective amount ofthe compound